Antagonists of gonadotropin releasing hormone

ABSTRACT

There are disclosed compounds of formula (I) ##STR1## and pharmaceutically acceptable salts thereof which are useful as antagonists of GnRH and as such may be useful for the treatment of a variety of sex-hormone related conditions in both men and women.

This application is a 371 of PCT/US97/08432, filed May 16, 1997 whichclaims benefit of Provisional Appl. 60/017,959 filed May 20, 1996.

BACKGROUND OF THE INVENTION

The gonadotropin-releasing hormone (GnRH), also referred to asluteinizing hormone-releasing hormone (LHRH), is a decapeptide thatplays a key role in human reproduction. The hormone is released from thehypothalamus and acts on the pituitary gland to stimulate thebiosynthesis and secretion of luteinizing hormone (LH) andfollicle-stimulating hormone (FSH). LH released from the pituitary glandis primarily responsible for the regulation of gonadal steroidproduction in both sexes, whereas FSH regulates spermatogenesis in malesand follicular development in females. GnRH agonists and antagonistshave proven effective in the treatment of certain conditions whichrequire inhibition of LH/FSH release. In particular, GnRH-basedtherapies have proven effective in the treatment of endometriosis,uterine fibroids, polycystic ovarian disease, precocious puberty andseveral gonadal steroid-dependent neoplasia, most notably cancers of theprostate, breast and ovary. GnRH agonists and antagonists have also beenutilized in various assisted fertilization techniques and have beeninvestigated as a potential contraceptive in both men and women. Theyhave also shown possible utility in the treatment of pituitarygonadotrophe adenomas, sleep disorders such as sleep apnea, irritablebowel syndrome, premenstrual syndrome, benign prostatic hyperplasia,hirsutism, as an adjunct to growth hormone therapy in growth hormonedeficient children, and in murine models of lupus. The compounds of theinvention may also be used in combination with bisphosphonates(bisphosphonic acids) and other agents, such as growth hormonesecretagogues, e.g. MK-0677, for the treatment and the prevention ofdisturbances of calcium, phosphate and bone metabolism, in particular,for the prevention of bone loss during therapy with the GnRH antagonist,and in combination with estrogens, progesterones, antiestrogens,antiprogestins and/or androgens for the prevention or treatment of boneloss or hypogonadal symptoms such as hot flashes during therapy with theGnRH antagonist.

Additionally, a compound of the present invention may be co-administeredwith a 5α-reductase 2 inhibitor, such as finasteride or epristeride; a5α-reductase 1 inhibitor such as 4,7β-dimethyl-4-aza-5α-cholestan-3-one,3-oxo-4-aza-4,7β-dimethyl-16β-(4-chlorophenoxy)-5α-androstane, and3-oxo-4-aza-4,7β-dimethyl-16β-(phenoxy)-5α-androstane as disclosed in WO93/23420 and WO 95/11254; dual inhibitors of 5α-reductase 1 and5α-reductase 2 such as3-oxo-4-aza-17β-(2,5-trifluoromethylphenyl-carbamoyl)-5α-androstane asdisclosed in WO 95/07927; antiandrogens such as flutamide, casodex andcyproterone acetate, and alpha-i blockers such as prazosin, terazosin,doxazosin, tamsulosin, and alfuzosin.

Further, a compound of the present invention may be used in combinationwith growth hormone, growth hormone releasing hormone or growth hormonesecretagogues, to delay puberty in growth hormone deficient children,which will allow them to continue to gain height before fusion of theepiphyses and cessation of growth at puberty.

Current GnRH antagonists are GnRH-like decapeptides which are generallyadministered intravenously or subcutaneously presumably because ofnegligible oral activity. These have amino acid substitutions usually atpositions one, two, three, six and ten.

Non-peptide GnRH antagonists offer the possible advantage of oraladminstration. Non-peptide GnRH antagonists have been described inEuropean Application 0 219 292 and in De, B. et al., J. Med. Chem., 32,2036-2038 (1989), in WO 95/28405, WO 95/29900 and EP 0679642 all toTakeda Chemical Industries, Ltd.

Arylquinolone analogs have been described in the art and include thosedescribed in the following patents, patent applications and journalarticles. JP-A-63-295561 discloses a class of 3-phenyl-2(1H)-quinolonederivatives, substituted at the 4-position by an unsubstituted straightor branched alkoxy group and at the 7-position by an unsubstitutedstraight or branched alkoxy group. These compounds are alleged toexhibit a strong inhibitory action on bone resorption and a stimulatoryeffect on ossification, and thus to be useful as therapeutic agents forthe prevention and treatment of osteoporosis.

J. Heterocycl. Chem., 1989, 26, 281 discloses a range of3-(2-methoxyphenyl)-2(1H)-quinolones possessing a halogen substituent inthe 6- or 7-position and an optional carboxylic acid substituent at the4-position. A family of 3-phenyl-2(IH)-quinolone derivatives,substituted at the 4-position by an amino or benzylamino group and atthe 7-position by a methyl or methoxy group, is described in Monatsh.Chem., 1982, 113, 751 and Vestn. Slov. Kem. Drus., 1986, 33, 271.

WO 93/10783 and WO 93/11115 disclose a class of 2-(1H)-quinolonederivatives, substituted at the 3-position by an optionally substitutedaryl substituent and are selective non-competitive antagonists of NMDAreceptors and/or are antagonists of AMPA receptors, and are therefore ofutility in the treatment of conditions, such as neurodegenerativedisorders, convulsions or schizophrenia.

FR 2711992-Al discloses quinolone derivatives which are allegedly usefulas antagonists of platelet activating factor.

SUMMARY OF THE INVENTION

The present invention relates to compounds which are non-peptideantagonists of GnRH which can be used to treat a variety of sex-hormonerelated conditions in men and women, to methods for their preparation,and to methods and pharmaceutical compositions containing said compoundsfor use in mammals.

Because of their activity as antagonists of the hormone GnRH, thecompounds of the present invention are useful to treat a variety ofsex-hormone related conditions in both men and women. These conditionsinclude endometriosis, uterine fibroids, polycystic ovarian disease,hirsutism, precocious puberty, gonadal steroid-dependent neoplasias suchas cancers of the prostate, breast and ovary, gonadotrophe pituitaryadenomas, sleep apnea, irritable bowel syndrome, premenstrual syndromeand benign prostatic hypertophy. They are also useful as an adjunct totreatment of growth hormone deficiency and short stature, and for thetreatment of systemic lupus erythematosis. Further, the compounds of theinvention may be useful in in vitro fertilization and as contraceptives.The compounds may also be useful in combination with androgens,estrogens, progesterones, antiestrogens and antiprogestogens for thetreatment of endometriosis, fibroids and in contraception. They may alsobe useful in combination with testosterone or other androgens orantiprogestogens in men as a contraceptive. The compounds may also beused in combination with an angiotensin-converting enzyme inhibitor suchas Enalapril or Captopril, an angiotensin II-receptor antagonist such asLosartan or a renin inhibitor for the treatment of uterine fibroids.Additionally, the compounds of the invention may also be used incombination with bisphosphonates (bisphosphonic acids) and other agents,for the treatment and the prevention of disturbances of calcium,phosphate and bone metabolism, in particular, for the prevention of boneloss during therapy with the GnRH antagonist, and in combination withestrogens, progesterones and/or androgens for the prevention ortreatment of bone loss or hypogonadal symptoms such as hot flashesduring therapy with the GnRH antagonist.

Additionally, a compound of the present invention may be co-administeredwith a 5α-reductase 2 inhibitor, such as finasteride or epristeride; a5α-reductase 1 inhibitor such as 4,7β-dimethyl-4-aza-5α-cholestan-3-one,3-oxo-4-aza-4,7β-dimethyl-16β-(4-chlorophenoxy)-5α-androstane, and3-oxo-4-aza-4,7β-dimethyl-16β-(phenoxy)-5α-androstane as disclosed in WO93/23420 and WO 95/11254; dual inhibitors of 5α-reductase I and5α-reductase 2 such as3-oxo-4-aza-17β-(2,5-trifluoromethylphenyl-carbamoyl)-5α-androstane asdisclosed in WO 95/07927; antiandrogens such as flutamide, casodex andcyproterone acetate, and alpha-1 blockers such as prazosin, terazosin,doxazosin, tamsulosin, and alfuzosin.

Further, a compound of the present invention may be used in combinationwith growth hormone, growth hormone releasing hormone or growth hormonesecretagogues, to delay puberty in growth hormone deficient children,which will allow them to continue to gain height before fusion of theepiphyses and cessation of growth at puberty.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of the general formula##STR2## wherein:

A is a bond, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, C₂ -C₆ alkenyl,substituted C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, substituted C₂ -C₆ alkynyl,C₁ -C₆ alkoxy, substituted C₁ -C₆ alkoxy;

B is a bond, C₁ -C₄ alkyl, substituted C₁ -C₄ alkyl;

X is O, S, SO, SO₂, NR₁₂, C(R₋₋ R₁₄) or can be absent;

R₁ is H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl,substituted C₃ -C₆ cycloalkyl, aryl, substituted aryl, C₁ -C₆ aralkyl,substituted C₁ -C₆ aralkyl;

R₂, R₃ and R₄ are independently H, C₁ -C₆ alkyl, substituted C₁ -C₆alkyl, C₂ -C₆ alkenyl, substituted C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,substituted C₂ -C₆ alkynyl, CN, nitro, C₁ -C₃ perfluoroalkyl, C₁ -C₃perfluoroalkoxy, aryl, substituted aryl, C₁ -C₆ aralkyl, substituted C₁-C₆ aralkyl, R₁₅ O(CR₁₃ R₁₄)_(p) --, R₁₆ C(O)O(CR₁₃ R₁₄)_(p) --, R₁₅OC(O)(CR₁₃ R₁₄)_(p) --, --(CR₁₃ R₁₄)_(p) S(O)_(n) R₁₂, (CR₁₃ R₁₄)_(p)C(O)NR₁₇ R₁₈, --(CR₁₃ R₁₄)_(p) NR₁₇ C(O)R₁₆, --(CR₁₃ R₁₄)_(p) N(R₁₇ R₁₈)or halogen;

R₂ and R₃ taken together form a carbocyclic ring, saturated orunsaturated, of 3-7 carbon atoms or a heterocyclic ring containing 1-3heteroatoms selected from N, O and S;

R₅, R₆, R₇ and R₈, independently are H, halogen, C₁ -C₆ alkyl,substituted C₁ -C₆ alkyl, C₂ -C₆ alkenyl, substituted C₂ -C₆ alkenyl, C₂-C₆ alkynyl, substituted C₂ -C₆ alkynyl, aryl, substituted aryl, C₁ -C₆aralkyl, substituted C₁ -C₆ aralkyl, heteroaryl, C₁ -C₆ heteroaralkyl,substituted heteroaryl, substituted C₁ -C₆ heteroaralkyl, C₁ -C₃perfluoroalkyl, C₁ -C₃ perfluoroalkoxy, R₁₅ O(CR₁₃ R₁₄)_(p) --, --(CR₁₃R₁₄)_(p) CN, --(CR₁₃ R₁₄)_(p) SO_(n) R₁₂, --(CR₁₃ R₁₄)_(p) SO₂ N(R₁₇R₁₈), --(CR₁₃ R₁₄)_(p) N(R₁₇ R₁₈), --(CR₁₃ R₁₄)_(p) N(R₁₇)C(O)R₁₆,--(CR₁₃ R₁₄)_(p) N(R₁₇)C(O)N(R₁₇ R₁₈), --(CR₁₃ R₁₄)_(p) N(R₁₇)SO₂ N(R₁₇R₁₈), --(CR₁₃ R₁₄)_(p) N(R₁₇)SO₂ R₁₂, --(CR₁₃ R₁₄)_(p) C(O)OR₁₅, --(CR₁₃R₁₄)_(p) OC(O)R₁₆, --(CR₁₃ R₁₄)_(p) C(O)N(R₁₇ R₁₈) --(CR₁₃ R₁₄)_(p)OC(O)N(R₁₇ R₁₈), --(CR₁₃ R₁₄)_(p) N(R₁₇)C(O)OR₁₅, or ##STR3##

R₉ and R_(9a) are independently H, C₁ -C₆ alkyl, substituted C₁ -C₆alkyl, aryl, C₁ -C₆ aralkyl, substituted aryl, substituted C₁ -C₆aralkyl; or

R₁₀ is H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, aryl, C₁ -C₆ aralkyl,substituted aryl, substituted C₁ -C₆ aralkyl; or

R₁₁ is H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, --(CR₁₃ R₁₄)_(p)C(O)OR₁₅ ; or

R₉ and R_(9a) can be taken together to form a carbocyclic ring,saturated or unsaturated, of 3-7 variously substituted carbon atoms, or;

R₉ and R₁₀ can be taken together to form a heterocyclic ring, saturatedor unsaturated, of 4-7 atoms containing 1-3 heteroatoms selected from O,N, and S, or;

(R₉ and R₁₀) and (R_(9a) and R₁₁) can be taken together to form aheterobicyclic ring, with each ring being independently saturated orunsaturated, of 4-7 atoms containing 1-3 heteroatoms selected from O, N,and S;

R₁₂ is H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, aryl, substitutedaryl, C₁ -C₆ aralkyl, substituted C₁ -C₆ aralkyl;

R₁₃ and R₁₄ are independently H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl,aryl, substituted aryl, C₁ -C₆ aralkyl, substituted C₁ -C₆ aralkyl;

R₁₅ is H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, aryl, substitutedaryl, C₁ -C₆ aralkyl, substituted C₁ -C₆ aralkyl; heteroaryl,substituted heteroaryl, C₁ -C₆ heteroaralkyl, substituted C₁ -C₆heteroaralkyl, or a heterocyclic ring containing 1-4 heteroatomsselected from O, N, and S;

R₁₆ is H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, aryl, substitutedaryl, C₁ -C₆ aralkyl, substituted C₁ -C₆ aralkyl; heteroaryl,substituted heteroaryl, C₁ -C₆ heteroaralkyl, substituted C₁ -C₆heteroaralkyl, or a heterocyclic ring containing 1-4 heteroatomsselected from O, N, and S;

R₁₇ and R₁₈ are independently H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl,C₃ -C₆ cycloalkyl, substituted C₃ -C₆ cycloalkyl, aryl, substitutedaryl, C₁ -C₆ aralkyl, substituted C₁ -C₆ aralkyl, heteroaryl,substituted heteroaryl, C₁ -C₆ heteroaralkyl, substituted C₁ -C₆heteroaralkyl; or taken together form a carbocyclic ring(s) of 4-7carbon atoms each or a heterocyclic ring containing 1-4 heteroatomsselected from O, N, and S;

R₁₉ is H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl or --CN;

n is 0, 1, or 2;

p is 0, 1, 2, 3 or 4

the alkyl, cycloalkyl, alkenyl and alkynyl substituents are selectedfrom C₁ -C₆ alkyl, C₃ -C₇ cycloalkyl, aryl, substituted aryl, aralkyl,substituted aralkyl, hydroxy, oxo, cyano, C₁ -C₆ alkoxy, fluoro,C(O)OR₁₁, aryl C₁ -C₃ alkoxy, substituted aryl C₁ -C₃ alkoxy, and thearyl substituents are as defined for R₃, R₄ and R_(5;)

or a pharmaceutically acceptable addition salt and/or hydrate thereof,or where applicable, a geometric or optical isomer or racemic mixturethereof.

Unless otherwise stated or indicated, the following definitions shallapply throughout the specification and claims.

When any variable (e.g., aryl, heterocycle, R₁, etc.) occurs more thanone time in any constituent or in formula I, its definition on eachoccurrence is independent of its definition at every other occurrence.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

The term "alkyl" is intended to include both branched- andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, e.g., methyl (Me), ethyl (Et), propyl,butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decyl, undecyl, dodecyl,and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu),sec-butyl (s-Bu), tert-butyl (t-Bu), isopentane, isohexane, etc.

The term "halogen" or "halo" is intended to include fluorine, chlorine,bromine and iodine.

The term "aryl" includes phenyl and naphthyl. Preferably, aryl isphenyl.

The term "heterocycle" or "heterocyclic ring" is defined by allnon-aromatic, heterocyclic rings of 3-7 atoms containing 1-3 heteroatomsselected from N, O, and S, such as oxirane, oxetane, tetrahydrofuran,tetrahydropyran, pyrrolidine, piperidine, tetrahydropyridine,tetrahydropyrimidine, tetrahydrothiophene, tetrahydrothiopyran,morpholine, hydantoin, valerolactam, pyrrolidinone, and the like.

The term "heteroaryl" is intended to include the compounds shown below:##STR4## where Z is: O, S, or NR₁₂

In addition, it is well known to those skilled in the art that many ofthe foregoing heterocyclic groups can exist in more than one tautomericform. It is intended that all such tautomers be included within theambit of this invention.

The optical isomeric forms, that is mixtures of enantiomers, e.g.,racemates, or diastereomers as well as individual enantiomers ordiastereomers of the instant compound are included. These individualenantiomers are commonly designated according to the optical rotationthey effect by the symbols (+) and (-), (L) and (D), (1) and (d) orcombinations thereof. These isomers may also be designated according totheir absolute spatial configuration by (S) and (R), which stands forsinister and rectus, respectively.

The individual optical isomers may be prepared using conventionalresolution procedures, e.g., treatment with an appropriate opticallyactive acid, separating the diastereomers and then recovering thedesired isomer. In addition, the individual optical isomers may beprepared by asymmetric synthesis.

Additionally, a given chemical fomula or name shall encompasspharmaceutically acceptable addition salts thereof and solvates thereof,such as hydrates.

The compounds of the present invention, while effective themselves, maybe formulated and administered in the form of their pharmaceuticallyacceptable addition salts for purposes of stability, convenience ofcrystallization, increased solubility and other desirable properties.

The compounds of the present invention may be administered in the formof pharmaceutically acceptable salts. The term "pharmaceuticallyacceptable salt" is intended to include all acceptable salts. Examplesof acid salts are hydrochloric, nitric, sulfuric, phosphoric, formic,acetic, trifluoroacetic, propionic, maleic, succinic, malonic,methanesulfonic and the like which can be used as a dosage form formodifying the solubility or hydrolysis characteristics or can be used insustained release or prodrug formulations. Depending on the particularfunctionality of the compound of the present invention, pharmaceuticallyacceptable salts of the compounds of this invention include those formedfrom cations such as sodium, potassium, aluminum, calcium, lithium,magnesium, zinc, and from bases such as ammonia, ethylenediamine,N-methyl-glutamine, lysine, arginine, omithine, choline,N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine,N-benzylphenethylamine, diethylamine, piperazine,tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.These salts may be prepared by standard procedures, e.g. by reacting afree acid with a suitable organic or inorganic base, or alternatively byreacting a free base with a suitable organic or inorganic acid.

Also, in the case of an acid (--COOH) or alcohol group being present,pharmaceutically acceptable esters can be employed, e.g. methyl, ethyl,butyl, acetate, maleate, pivaloyloxymethyl, and the like, and thoseesters known in the art for modifying solubility or hydrolysischaracteristics for use as sustained release or prodrug formulations.

The compounds of the present invention may have chiral centers otherthan those centers whose stereochemistry is depicted in formula I, andtherefore may occur as racemates, racemic mixtures and as individualenantiomers or diastereomers, with all such isomeric forms beingincluded in the present invention as well as mixtures thereof.Furthermore, some of the crystalline forms for compounds of the presentinvention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe instant invention may form solvates with water or common organicsolvents. Such solvates are encompassed within the scope of thisinvention.

As used herein, the term "composition" is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The compounds of the invention are prepared by the following reactionschemes. All substituents are as defined above unless indicatedotherwise. ##STR5##

Reaction Scheme A

As shown in reaction Scheme A, treatment of amino ester (1) with an arylacetyl chloride (2) in an inert organic solvent such as dicloroethane,chloroform, methylene chloride or the like at a temperature of 25°-80°C. for a period of 30 minutes to 4 hours gives the corresponding amide(4). Alternatively, treatment of amine (1) and an arylacetic acid (3)with the coupling reagent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC), 1,3-dicyclohexylcarbodiimide (DCC) or the like withor without 1-hydroxybenzotriazole (HOBt) and a tertiary amine base suchas N-methylmorpholine (NMM), triethylamine or the like in an inertorganic solvent such as methylene chloride, chloroform,dimethylformamide, or mixtures thereof at or near room temperature for aperiod of 3-24 hours provides the corresponding amide derivative (4).Cyclization of amide (4) is effected by treatment with a strong basesuch as sodium bis(trimethylsilyl)amide, lithiumbis(trimethylsilyl)amide or the like in an inert organic solvent such astetrahydrofuran at a temperature of -20°-25° C. for a period of 2-4hours to give quinolone (5). ##STR6##

Reaction Scheme B

As shown in reaction Scheme B, treatment of the 4-hydroxyquinolone (5)with an alkylamine containing a halogen or sulfonate leaving group (6)and a suitable base such as potassium carbonate, sodium carbonate,sodium bicarbonate, DBU or the like along with the catalyst sodiumiodide in an inert organic solvent such as N,N-dimethylformamide,tetrahydrofuran, acetonitrile or the like at or around 80° C. for aperiod of 4-24 hours provides the ether derivative (7). As analternative, a suitably protected amino alcohol (8) may be coupled to(5) by treatment under Mitsunobu reaction conditions withtriphenylphosphine and an activating agent such as diethylazodicarboxylate, disopropyl azodicarboxylate or the like in an inertsolvent such as tetrahydrofuran, toluene, chlorobenzene or the like atambient temperature for a period of 4-64 hours to give (7).

After coupling, the amino group can be deprotected by any methodsuitable to the protecting group used and compatible with thefunctionality present in (7). For example, a t-butyl carbamate group canbe removed by treatment with a protic acid such as trifluoroacetic acid,with or without added anisole, in an inert organic solvent such asmethylene chloride at ambient temperature for a period of 30 minutes to4 hours to provide the corresponding amine. ##STR7##

Reaction Scheme C

As shown in reaction Scheme C, the 4-hydroxyquinolone structure (5) maybe modified by conversion to a sulfonate leaving group such as thetrifluoromethanesulfonate (9) upon treatment withtrifluoromethane-sulfonic anhydride in an inert organic solvent such asmethylene chloride and an amine base such as diazabicycloundecene,2,6-lutidine, pyridine or the like at or below room temperature for aperiod of 30 minutes to 2 hours. Reaction of (9) with an appropriatethiol (10) and an amine base such as diisopropylethylamine,triethylamine or the like in an inert organic solvent such asN,N-dimethylformamide at or below room temperature for a period of 4-24hours gives the thioether analog (11). ##STR8##

Reaction Scheme D

As shown in reaction Scheme D, nitro groups appended to thesestructures, such as in (12), can be reduced to the corresponding amines(13) by treatment with hydrazine and a reduction catalyst such as iron(III) chloride and carbon in an inert organic solvent such as methanol,ethanol or the like at a temperature of 65°-100° C. for a period of 5-20hours. Alternatively, treatment of (12) with tin(II)chloride dihydratein a polar solvent such as ethanol or methanol at a temperature of70°-80° C. for a period of 30 minutes to 4 hours gives the reduced,amino derivative (13). ##STR9##

Reaction Scheme E

As shown in reaction Scheme E, amines such as (13) can be converted tothe corresponding urea derivatives (14) by treatment with an appropriateacylating agent such as phosgene, triphosgene, carbonyldiimidazole orthe like, with or without an amine base such as pyridine in an inertorganic solvent such as methylene chloride, chloroform, dicloroethane orthe like together with the desired primary or secondary amine at 0°-25°C. for a period of 1-48 hours. ##STR10##

Reaction Scheme F

As shown in reaction Scheme F. amines such as (15) can be converted tothe corresponding amide (18) or sulfonamide derivatives (19) bytreatment with an appropriate acylating agent such as an acetylchloride, acid anhydride, sulfonylchloride, sulfonic anhydride or thelike, with or without an amine base such as pyridine, in an inertorganic solvent such as methylene chloride, chloroform, dichloroethane,benzene, toluene, chlorobenzene or the like at 0°-100° C. for a periodof 1-10 hours. ##STR11##

Reaction Scheme G

As shown in Scheme G, iodides such as (20) can be converted to thecorresponding amide (22) by treatment with an appropriate amine (21) anda palladium catalyst such asdichlorobis(triphenylphosphine)palladium(II) in the presence of an aminebase such as triethylamine in an inert organic solvent such asN,N-dimethylformamide, or the like, under an atmosphere of carbonmonoxide at 90° C. for a period of 5-25 hours. ##STR12##

Reaction Scheme H

As shown in Reaction Scheme H, iodide (20) can be coupled with alkyl-,vinyl-, aryl- and heteroaryl-stannanes (23) using an appropriatepalladium catalyst such as dichlorobis(triphenylphosphine) palladium(II)in an inert organic solvent such as N,N-dimethyl formamide, toluene, orthe like, at a temperature of 80-110° C. with or without the presence ofcarbon monoxide to provide ketones (24) and carbon-linked derivatives(25), respectively. ##STR13##

Reaction Scheme I

As shown in Scheme I, the allyl derivative (26) can be converted toprimary alcohol (27) by treatment with borane or a suitable alkylboranereagent in an inert solvent such as tetrahydrofuran followed by exposureto a mild oxidant such as hydrogen peroxide. Alcohols such as (27) canbe further oxidized by treatment with tetrapropylammoniumperruthenate(VII) and 4-methylmorpholine-N-oxide or similarly mildoxidants in an organic solvent such as methylene chloride at roomtemperature for a period of 1 to 5 hours to give the correspondingaldehyde. Further oxidation to the carboxylic acid can be conducted witha strong oxidant such as potassium permanganate to give acids such as(28). ##STR14##

Reaction Scheme J

As shown in Scheme J, the allyl derivative (26) can be converted to thediol (29) by treatment with osmium tetraoxide with or without aco-oxidant such as 4-methylmorpholine-N-oxide in an inert solvent suchas tetrahydrofuran, tert-butanol, water or mixtures thereof at roomtemperature for a period of 15 minutes to 5 hours. Diols such as (29)can be further oxidized by treatment with lead (IV) acetate in an inertsolvent such as methanol pyridine or mixtures thereof at roomtemperature for a period of 10 minutes to 2 hours to give thecorresponding aldehyde derivative. Further oxidation to the carboxylicacid can be conducted with a strong oxidant such as potassiumpermanganate to give acids such as (30).

Alternatively, treatment of diol (29) with a strong oxidant such aspotassium permanganate, ruthenium tetraoxide or the like can give thebenzoic acid product (31) directly. ##STR15##

Reaction Scheme K

As shown in Scheme K, treatment of carboxylic acid (32) and anappropriate amine such as (33) with the coupling reagent1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC),1,3-dicyclohexylcarbodiimide (DCC) or the like with or without1-hydroxybenzotriazole (HOBt) and a tertiary amine base such asN-methylmorpholine NMM), triethylamine or the like in an inert organicsolvent such as methylene chloride, chloroform, dimethylformamide, ormixtures thereof at or near room temperature for a period of 3-24 hoursprovides the corresponding amide derivative (34). ##STR16##

Reaction Scheme L

As shown in Scheme L, amines such as (35) can undergo reductiveamination with carbonyl -containing compounds like (36) by treating thepair with a dessicant such as molecular seives or magnesium sulfate andan acid catalyst such as acetic acid in an inert organic solvent such asmethanol, chloroform or the like followed by a reducing agent such assodium cyanoborohydride, sodium borohydride, or hydrogen and anappropriate metal catalyst to give derivative (37).

The compounds of the present invention are useful in the treatment ofvarious sex-hormone related conditions in men and women. This utility ismanifested in their ability to act as antagonists of the neuropeptidehormone GnRH as demonstrated by activity in the following in vitroassays.

Human GnRH receptor binding assay

Crude membranes prepared from CHO cells expressing human GnRH receptorswere the sources for GnRH receptor. [¹²⁵ I]Buserelin (a peptidyl GnRHanalog) was used as the radiolabelled ligand. The binding activity wasdetermined as an IC₅₀ which is the antagonist concentration required toinhibit the specific binding of [¹²⁵ I]buserelin to GnRH receptors by50%.

Rat pituitary GnRH receptor binding assay

Crude plasma membranes prepared from rat pituitary tissues wereincubated in a Tris.HCl buffer (50 mM, PH. 7.5) containing bovine serumalbumin (0.1%), [I-125]D-t-Bu-Ser6-Pro9-ethyl amide-GnRH, and thedesired concentration of a test compound. The assay mixtures wereincubated at 4° C. for 90-120 minutes followed by rapid filtration andrepeated washings through a glass fiber filter. The radioactivity ofmembrane bound radioligands was determined in a gamma-counter. From thisdata, the IC₅₀ of the radioligand binding to GnRH receptors in thepresence of test compound was estimated.

Inhibition of LH release assay

Active compounds from the GnRH receptor binding assay were furtherevaluated with an in vitro LH release assay to confirm their antagonistactivity (blocking OnRH-induced LH release).

1. Sample Preparation

The compounds to be assayed were dissolved and diluted in DMSO. Thefinal concentration of DMSO in the incubation medium was 0.5%.

2. Assay

The Wistar male rats (150-200 grams) were obtained from Charles RiverLaboratories (Wilmington, Mass.). Rats were maintained at a constanttemperature (25° C.) on a 12-hr light, 12-hr dark cycle. Rat chow andwater were available ad libitum. The animals were sacrificed bydecapitation and pituitary glands were aseptically removed and placed inHank's Balanced Salt Solution (HBSS) in a 50-ml polypropylene centrifugetube. The collection tube was centrifuged for 5 min at 250×g, and HBSSwas removed by aspiration. Pituitary glands were transferred to adisposable petri plate and minced with a scalpel. The minced tissue wasthen transferred to a 50-ml disposable centrifuge tube by suspending thetissue fragments in three successive 10-mL aliquots of HBSS containing0.2% collagenase and 0.2% hyaluronidase. The cell dispersion was carriedout in a water bath at 37° C. with gentle stirring for 30 min. At theend of the incubation, the cells were aspirated 20 to 30 times with apipet and the undigested pituitary fragments were allowed to settle for3 to 5 min. The suspended cells were removed by aspiration, and thensubjected to a 1200×g centrifugation for 5 min. The cells were thenresuspended in Culture medium. The undigested pituitary fragments weretreated with 30 mL aliquots of the digestion enzymes as above for atotal of 3 digestions with the collagenase/hyaluronidase mixture. Theresulting cell suspensions were pooled, counted and diluted to aconcentration of 3×10⁵ cells/mL, and 1.0 mL of this suspension wasplaced in each well of a 24-well tray (Costar, Cambridge, Mass.). Cellswere maintained in a humidified 5% CO₂ -95% air atmosphere at 37° C. for3 to 4 days. The culture medium consisted of DMEM containing 0.37%NaHCO₃, 10% horse serum, 2.5% fetal bovine serum, 1% non-essential aminoacids, 1% glutamine, and 0.1% gentamycin. On the day of an experiment,cells were washed three times 1 1/2 hrs prior to and two more timesimmediately before the start of the experiment with DMEM containing0.37% NaHCO₃, 10% horse serum, 2.5% fetal bovine serum, 1% non-essentialamino acids(100×), 1% glutamine(100×), 1% Penicillin/Streptomycin(10,000Units of Penicillin and 10,000 micrograms of Streptomycin per ml), and25 mM HEPES, pH 7.4. LH release was initiated by adding 1 ml of freshmedium containing test compounds in the presence of 2 nM GnRH to eachwell in duplicate. Incubation was carried out at 37° C. for 3 hr. Afterincubation, medium was removed and centrifuged at 2,000×g for 15 min toremove any cellular material. The supernatant fluid was removed andassayed for LH content with a double antibody RIA procedure usingmaterials obtained from Dr. A. F. Parlow (Harbor-UCLA Medical Center,Torrance, Calif.).

The compounds of formula I are useful in a number of areas affected byGnRH. They may be useful in sex-hormone related conditions, sex-hormonedependent cancers, benign prostatic hypertrophy or myoma of the uterus.Sex-hormone dependent cancers which may benefit from the administrationof the compounds of this invention include prostatic cancer, uterinecancer, breast cancer and pituitary gonadotrophe adenomas. Othersex-hormone dependent conditions which may benefit from theadministration of the compounds of this invention include endometriosis,polycystic ovarian disease, uterine fibroids and precocious puberty. Thecompounds may also be used in combination with an angiotensin-convertingenzyme inhibitor such as Enalapril or Captopril, an angiotensinII-receptor antagonist such as Losartan or a renin inhibitor for thetreatment of uterine fibroids.

The compounds of the invention may also be useful for controllingpregnancy, as a contraceptive in both men and women, for in vitrofertilization, in the treatment of premenstrual syndrome, in thetreatment of lupus erythematosis, in the treatment of hirsutism, in thetreatment of irritable bowel syndrome and for the treatment of sleepdisorders such as sleep apnea.

A further use of the compounds of this invention is as an adjunct togrowth hormone therapy in growth hormone deficient children. Thecompounds may be administered with growth hormone or a compound whichincreases the endogenous production or release of growth hormone.Certain compounds have been developed which stimulate the release ofendogenous growth hormone. Peptides which are known to stimulate therelease of endogenous growth hormone include growth hormone releasinghormone, the growth hormone releasing peptides GHRP-6 and GHRP-1(described in U.S. Pat. No. 4,411,890, PCT Patent Pub. No. WO 89/07110,and PCT Patent Pub. No. WO 89/07111) and GHRP-2 (described in PCT PatentPub. No. WO 93/04081), as well as hexarelin (J. Endocrinol Invest.,15(Suppl 4), 45 (1992)). Other compounds which stimulate the release ofendogenous growth hormone are disclosed, for example, in the following:U.S. Pat. Nos. 3,239,345; 4,036,979; 4,411,890; 5,206,235; 5,283,241;5,284,841; 5,310,737; 5,317,017; 5,374,721; 5,430,144; 5,434,261;5,438,136; EPO Patent Pub. No. 0,144,230; EPO Patent Pub. No. 0,513,974;PCT Patent Pub. No. WO 94/07486; PCT Patent Pub. No. WO 94/08583; PCTPatent Pub. No. WO 94111012; PCT Patent Pub. No. WO 94/13696; PCT PatentPub. No. WO 94/19367; PCT Patent Pub. No. WO 95/03289; PCT Patent Pub.No. WO 95/03290; PCT Patent Pub. No. WO 95/09633; PCT Patent Pub. No. WO95/11029; PCT Patent Pub. No. WO 95/12598; PCT Patent Pub. No. WO95/13069; PCT Patent Pub. No. WO 95/14666; PCT Patent Pub. No. WO95/16675; PCT Patent Pub. No. WO 95/16692; PCT Patent Pub. No. WO95/17422; PCT Patent Pub. No. WO 95/17423; Science, 260, 1640-1643 (Jun.11, 1993); Ann. Rep. Med. Chem., 28, 177-186 (1993); Bioorg. Med. Chem.Ltrs., 4(22), 2709-2714 (1994); and Proc. Natl. Acad. Sci. USA 92,7001-7005 (July 1995).

Representative preferred growth hormone secretagoues employed in thepresent combination include the following:

1)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(1H-indol-3-yl)ethyl]-2-amino-2-methyl-propanamide;

2)N-[1(R)-[(1,2-Dihydro-1-methanecarbonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(1H-indol-3-yl)ethyl]-2-amino-2-methyl-propanamide;

3)N-[1(R)-[(1,2-Dihydro-1-benzenesulfonylspiro[3H-indole-3,4'-piperidin]-1-yl)carbonyl]-2-(1H-indol-3-yl)ethyl]-2-amino-2-methyl-propanamide;

4)N-[1(R)-[(3,4-Dihydro-spiro[2H-1-benzopyran-2,4'-piperidin]-1'-yl)carbonyl]-2-(1H-indol-3-yl)ethyl]-2-amino-2-methylpropanamide;

5)N-[1(R)-[(2-Acetyl-1,2,3,4-tetrahydrospiro[isoquinolin-4,4'-piperidin]-1'-yl)carbonyl]-2-(indol-3-yl)ethyl]-2-amino-2-methyl-propanamide;

6)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide;

7)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamidemethanesulfonate;

8)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(2',6'-difluorophenylmethyloxy)ethyl]-2-amino-2-methylpropanamide;

9)N-[1(R)-[(1,2-Dihydro-1-methanesulfonyl-5-fluorospiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide;

10)N-[1(S)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethylthio)ethyl]-2-amino-2-methylpropanamide;

11)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-3-phenylpropyl]-2-amino-2-methyl-propanamide;

12)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-3-cyclohexylpropyl]-2-amino-2-methyl-propanamide;

13)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-4-phenylbutyl]-2-amino-2-methyl-propanamide;

14)N-[1(R)-[(1,2-Dihydro-1-methanesulfonylspiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(5-fluoro-1H-indol-3-yl)ethyl]-2-amino-2-methylpropanamide;

15)N-[1(R)-[(1,2-Dihydro-1-methanesulfonyl-5-fluorospiro[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(5-fluoro-1H-indol-3-yl)ethyl]-2-amino-2-methylpropanamide;

16)N-[1(R)-[(1,2-Dihydro-1-(2-ethoxycarbonyl)methylsulfonylspiro-[3H-indole-3,4'-piperidin]-1'-yl)carbonyl]-2-(1H-indol-3-yl)ethyl]-2-amino-2-methylpropanamide;

17)N-[1(R)-[(1,2-Dihydro-1,1-dioxospiro[3H-benzothiophene-3,4'-piperidin]-1'-yl)carbonyl]-2-(phenylmethyloxy)ethyl]-2-amino-2-methylpropanamide;

and pharmaceutically acceptable salts thereof.

The compounds of the invention may also be used in combination withbisphosphonates (bisphosphonic acids) and other agents, such as growthhormone secretagogues, e.g. MK-0677, for the treatment and theprevention of disturbances of calcium, phosphate and bone metabolism, inparticular, for the prevention of bone loss during therapy with the GnRHantagonist, and in combination with estrogens, progesterones and orandrogens for the prevention or treatment of bone loss or hypogonadalsymptoms such as hot flashes during therapy with the GnRH antagonist.

Bisphosphonates (bisphosphonic acids) are known to inhibit boneresorption and are useful for the treatment of bone lithiasis asdisclosed in U.S. Pat. No. 4,621,077 to Rosini, et al.

The literature discloses a variety of bisphosphonic acids which areuseful in the treatment and prevention of diseases involving boneresorption. Representative examples may be found in the following: U.S.Pat. Nos. 3,251,907; 3,422,137; 3,584,125; 3,940,436; 3,944,599;3,962,432; 4,054,598; 4,267,108; 4,327,039; 4,407,761; 4,578,376;4,621,077; 4,624,947; 4,746,654; 4,761,406; 4,922,007; 4,942,157;5,227,506; 5,270,365; EPO Patent Pub. No. 0,252,504; and J. Org. Chem.,36, 3843 (1971).

The preparation of bisphosphonic acids and halo-bisphosphonic acids iswell known in the art. Representative examples may be found in the abovementioned references which disclose the compounds as being useful forthe treatment of disturbances of calcium or phosphate metabolism, inparticular, as inhibitors of bone resorption.

Preferred bisphosphonates are selected from the group of the followingcompounds: alendronic acid, etidrononic acid, clodronic acid, pamidronicacid, tiludronic acid, risedronic acid,6-amino-1-hydroxy-hexylidene-bisphosphonic acid, and1-hydroxy-3(methylpentylamino)-propylidene-bisphosphonic acid; or anypharmaceutically acceptable salt thereof. A particularly preferredbisphosphonate is alendronic acid (alendronate), or a pharmaceuticallyacceptable salt thereof. An especially preferred bisphosphonate isalendronate sodium, including alendronate sodium trihydrate. Alendronatesodium has received regulatory approval for marketing in the UnitedStates under the trademark FOSAMAX®.

Additionally, a compound of the present invention may be co-administeredwith a 5α-reductase 2 inhibitor, such as finasteride or epristeride; a5α-reductase 1 inhibitor such as 4,7β-dimethyl-4-aza-5α-cholestan-3-one,3-oxo-4-aza-4,7β-dimethyl-16β-(4-chlorophenoxy)-5α-androstane, and3-oxo-4-aza-4,7β-dimethyl-16β-(phenoxy)-5α-androstane as disclosed in WO93/23420 and WO 95/11254; dual inhibitors of 5α-reductase 1 and5α-reductase 2 such as3-oxo-4-aza-17β-(2,5-trifluoromethylphenyl-carbamoyl)-5α-androstane asdisclosed in WO 95/07927; antiandrogens such as flutamide, casodex andcyproterone acetate, and alpha-1 blockers such as prazosin, terazosin,doxazosin, tamsulosin, and alfuzosin.

Further, a compound of the present invention may be used in combinationwith growth hormone, growth hormone releasing hormone or growth hormonesecretagogues, to delay puberty in growth hormone deficient children,which will allow them to continue to gain height before fusion of theepiphyses and cessation of growth at puberty.

For combination treatment with more than one active agent, where theactive agents are in separate dosage formulations, the active agents maybe administered separately or in conjunction. In addition, theadministration of one element may be prior to, concurrent to, orsubsequent to the administration of the other agent.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example, magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethyl-cellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy beans, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

Compounds of Formula I may also be administered in the form of asuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compound of Formula I are employed. (For purposesof this application, topical application shall include mouth washes andgargles.)

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wellknown to those of ordinary skill in the art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittent throughout the dosageregimen. Compounds of the present invention may also be delivered as asuppository employing bases such as cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound thereof employed. A physician or veterinarian of ordinary skillcan readily determine and prescribe the effective amount of the drugrequired to prevent, counter, arrest or reverse the progress of thecondition. Optimal precision in achieving concentration of drug withinthe range that yields efficacy without toxicity requires a regimen basedon the kinetics of the drug's availability to target sites. Thisinvolves a consideration of the distribution, equilibrium, andelimination of a drug. Preferably, doses of the compound of structuralformula I useful in the method of the present invention range from 0.01to 1000 mg per adult human per day. Most preferably, dosages range from0.1 to 500 mg/day. For oral administration, the compositions arepreferably provided in the form of tablets containing 0.01 to 1000milligrams of the active ingredient, particularly 0.01, 0.05, 0.1, 0.5,1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thepatient to be treated. An effective amount of the drug is ordinarilysupplied at a dosage level of from about 0.0002 mg/kg to about 50 mg/kgof body weight per day. The range is more particularly from about 0.001mg/kg to 10 mg/kg of body weight per day.

Advantageously, the active agent of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in dividend doses of two, three or four times daily.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

The following examples illustrate the preparation of some of thecompounds of the invention and are not to be construed as limiting theinvention disclosed herein.

EXAMPLE 1 ##STR17##1-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-4-(2-piperidin-2-yl-ethoxy)-1,2-dihydro-quinolin-6-yl]-3-pyridin-4-yl-urea

Step 1A 4-chloro-2-[2-(3,5-dimethylphenyl)-acetylamino]-5-nitro-benzoicacid methyl ester

To a suspension of 2-amino-4-chloro-5-nitrobenzoic acid methyl ester(989 mg in 15 mL of dry 1,2-dichloroethane) was added a solution of(3,5-dimethylphenyl)acetyl chloride (860 mg in 5 mL dry1,2-dichloroethane) and the mixture heated at reflux on an oil bath.After 18 hours, an additional portion of (3,5-dimethylphenyl)acetylchloride (274 mg in 1.5 mL dry 1,2-dichloroethane) was added and themixture heated at reflux for an additional 5 hours. At this time thereaction was cooled and the solvent removed in vacuo. Recrystallizationof the crude product from methanol gave the title compound (1.17 g).

Step 1B7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-6-nitro-1H-quinolin-2-one

To a solution of4-chloro-2-[2-(3,5-dimethylphenyl)-acetylamino]-5-nitrobenzoic acidmethyl ester (1.17 g in 10 mL dry tetrahydrofuran) at 0° C. was addeddropwise a solution of sodium bis(trimethylsilyl)amide (7.8 mL of a 1.0Msolution in tetrahydrofuran) and the mixture warmed to room temperature.After 2 hours, the reaction was quenched by the addition of 100 mL iced6N hydrochloric acid. The slurry was stirred for 10 minutes thenfiltered and washed (2×) with ice water and then cold acetonitrile. Theresidue was dried overnight at 45° C. to give the title compound (970mg).

Step 1C2-{2-[6-nitro-7-chloro-3-(3.5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid benzyl ester

To a solution of7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-6-nitro-1H-quinolin-2-one(13.5 g in 600 mL of N,N-dimethylformamide) was added 9.2 g of2-(2-hydroxyethyl)-piperidine-1-carboxylic acid benzyl ester and 14 g oftriphenylphosphine followed by 10.4 mL of diisopropyl azodicarboxylateand the mixture stirred at room temperature. After 24 hours, thesolvents were removed in vacuo and the residue resolvated in methylenechloride, washed with water and purified by flash chromatography onsilica gel (hexane:ethyl acetate, 90:10; then methylene chloride:ethylacetate, 95:5) to give the title compound (13.2 g).

Step 1D2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid benzyl ester

To a solution of2-{2-[6-nitro-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid benzyl ester (1.11 g in 30 mL ethanol) was added 2 mLtin(II)cloride dihydrate and the mixture heated to 70° C. on an oilbath. After 2 hours, the reaction was cooled to room temperature andquenched by the addition of 300 mL ice-water. The acidity of theresulting solution was adjusted to pH 8 by the addition of saturatedaqueous sodium bicarbonate and the mixture extracted (2×) with ethylacetate. The combined organics were washed with brine, dried over sodiumsulfate and concentrated in vacuo. Purification of the crude oil byflash chromatography on silica gel (methylene chloride:ethyl acetate,95:5) gave the title compound (0.50 g).

Step 1E2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(3-pyridin-4-yl-ureido)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid benzyl ester

To a solution of2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid benzyl ester (200 mg in 5 mL dry methylene chloride) at 0° C. wasadded phosgene (0.3 mL of a 1.93 M solution in toluene) followed by0.111 mL of triethylamine and the mixture stirred for 1 hour at 0° C. Atthis time, 188 mg of 4-aminopyridine was added and the mixture allowedto warm to room temperature. After 20 hours, the mixture was dilutedwith ethyl acetate (200 mL) and the reaction quenched by the addition of10% citric acid. The organic portion was concentrated in vacuo toprovide the crude title compound.

Step 1F1-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-4-(2-piperidin-2-yl-ethoxy)-1,2-dihydro-quinolin-6-yl]-3-pyridin-4-yl-urea

A solution of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(3-pyridin-4-yl-ureido)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid benzyl ester in 3 mL of a 30% solution of hydrobromic acid inacetic acid was stirred at room temperature for 3 hours thenconcentrated in vacuo. The residue was treated with saturated sodiumbicarbonate and then extracted with ethyl acetate. Purification of theconcentrate by flash chromatography on silica gel (methylenechloride:methanol:ammonium hydroxide, 96:3:1) gave the title compound.

PREPARATION OF SYNTHETIC INTERMEDIATES 2-amino-4-chloro-5-nitrobenzoicacid methyl ester

Step A: 2-acetylamino-4-chloro-5-nitrobenzoic acid methyl ester

To a solution of 3 mL conc. sulfuric acid and 0.40 mL of 90% nitric acidat 0° C. was added 2-acetylamino-4-chlorobenzoic acid methyl ester (1.5g) in three portions over a period of 20 minutes. This was stirred at 0°C. for 30 minutes then allowed to warm to room temperature for anadditional 1 hour. At this time the reaction was poured into 50 mL of anice/water mixture and extracted with ethyl acetate (3×50 mL). Thecombined organics were washed sequentially with water (2×50 mL), 10%sodium bicarbonate (2×50 mL) and brine (50 mL) then dried over magnesiumsulfate and concentrated in vacuo. Recrystallization of the crudeproduct from methanol gave the title compound (1.02 g).

Step B: 2-amino-4-chloro-5-nitrobenzoic acid methyl ester

To a solution of 2-acetylamino-4-chloro-5-nitrobenzoic acid methyl ester(1.02 g in 15 mL methanol) was added 1 mL of conc. sulfuric acid and themixture heated to reflux on an oil bath. After 1 hour, the mixture wasconcentrated in vacuo and the resulting solid dissolved in 200 mL ethylacetate. This was then washed with 10% sodium bicarbonate (2×100 mL) andbrine (100 mL) and the organics dried over magnesium sulfate. Theconcentrate was recrystallized from methanol to give the title compound(0.82 g).

(3,5-dimethylphenyl)acetyl chloride

To a solution of (3,5-dimethylphenyl)acetic acid (2.32 g in 25 mL drymethylene chloride) at 0° C. was added 0.055 mL N,N-dimethylformamidefollowed by the dropwise addition of 1.3 mL of oxalyl chloride. After 15minutes the mixture was warmed to room temperature and stiffed for anadditional 2 hours. Removal of the solvents in vacuo provided the titlecompound which was used without purification.

Following a procedure similar to that described above, the followingcompounds were prepared:

    ______________________________________                                          #STR18##                                                                    Ex. #   R.sub.6              m/e                                              ______________________________________                                          1A                                                                                                         546 (M #                                                                    + H)                                                - 1B                                                                                                      546 (M + H)                                       - 1C                                                                                                      552 (M + H)                                       - 1D                                                                                                      535 (M + H)                                       - 1E                                                                                                      567 (M + H)                                       - 1F                                                                                                      547 (M + H)                                       - 1G                                                                                                      560 (M + H)                                       - 1H                                                                                                      560 (M + H)                                       - 1I                                                                                                      574 (M + H)                                       - 1J                                                                                                      547 (M + H)                                       - 1K                                                                                                      560 (M + H)                                       - 1L                                                                                                      609 (M + H)                                       - 1M                                                                                                      547 (M + H)                                       - 1N                                                                                                      523 (M + H)                                       - 1O                                                                                                      537 (M + H)                                       - 1P                                                                                                      539 (M + H)                                       - 1Q                                                                                                      702 (M + H)                                       - 1R                                                                                                      547 (M + H)                                       - 1S                                                                                                      561 (M + H)                                       - 1T                                                                                                      561 (M + H)                                       - 1U                                                                                                      547 (M + H)                                    ______________________________________                                    

EXAMPLE 2 ##STR40##N-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-4-(2-piperidin-2-yl-ethoxy)-1,2-dihydroquinolin-6-yl]-2-pyridin-2-yl-acetamide

Step 2A2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(2-pyridin-2-yl-acetylamino)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a suspension of pyridin-2-yl-acetic acid hydrochloride (60 mg in 0.8mL methylene chloride) was added 0.051 mL triethylamine and the mixturestirred at room temperature for 10 minutes. At this time, 98 mg1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 69 mg1-hydroxybenzotriazole, and 60 mg2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (prepared essentially as described in Example 1)were added in order. After 22 hours, the mixture was diluted withmethylene chloride and extracted sequentially with water, 10% citricacid and brine. The organic portion was dried over sodium sulfate andthe concentrate purified by flash chromatography on silica gel(hexane:ethyl acetate, 1:1; then methylene chloride:10% ammoniumhydroxide in methanol, 95:5) to give the title compound, 55 mg.

Step 2BN-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-4-(2-piperidin-2-yl-ethoxy)-1,2-dihydroquinolin-6-yl]-2-pyridin-2-yl-acetamide

To a solution of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(2-pyridin-2-yl-acetylamino)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (55 mg in 4.0 mL methylene chloride) was added 2.0mL trifluoroacetic acid and the mixture stirred at room temperature.After 20 minutes, the mixture was concentrated in vacuo, resolvated in10% ammonium hydroxide in methanol and concentrated once again.Purification by flash chromatography on silica gel (methylenechloride:10% ammonium hydroxide in methanol, 95:5; then 90:10) gave thetitle compound, 40 mg.

Following a procedure similar to that described above, the followingcompounds were prepared:

    ______________________________________                                          #STR41##                                                                    Ex. #   R.sub.6              m/e                                              ______________________________________                                          2A                                                                                                         #STR42##                                          - 2B                                                                                                      #STR43##                                          - 2C                                                                                                      #STR44##                                          - 2D                                                                                                      536 (M + H)                                       - 2E                                                                                                      532 (M + H)                                       - 2F                                                                                                      582 (M + H)                                       - 2G                                                                                                      546 (M + H)                                       - 2H                                                                                                      #STR49##                                          - 2I                                                                                                      532 (M + H)                                       - 2J                                                                                                      547 (M + H)                                       - 2K                                                                                                     ##STR52##                                       ______________________________________                                    

EXAMPLE 3.1 ##STR53## 3-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-4-(2-piperidin-2-yl-ethoxy)-1,2-dihydroquinolin-6-yl]-1-methylimidazolidine-2,4-dione

Step 3.1A2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-nitro-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of 2-(2-hydroxyethyl)-piperidine-1-carboxylic acidtert-butyl ester (0.864 g in 38 mL dry tetrahydrofuran) was added 1.56 gof 7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-6-nitro- 1H-quinolin-2-onefollowed by 1.19 g of triphenylphosphine and the mixture stirred at roomtemperature. To this was added 0.72 mL of diethyl azodicarboxylate(DEAD) and stirring was continued for 64 hours. At this time thesolvents were removed in vacuo and the residue purified by flashchromatography on silica gel (hexane:ethyl acetate, 6:4) to give thetitle compound (1.56 g).

Step 3.1B 2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-1-piperidine-1-carboxylicacid tert-butyl ester To a solution of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-nitro-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acidtert-butyl ester (750 mg in 13 mL dry methanol) was added 18 mgiron(III)chloride hexahydrate followed by 100 mg activated carbon andthe mixture heated to reflux on an oil bath. After 15 minutes, hydrazine(0.169 mL) was added dropwise and the reaction allowed to proceed atreflux for 12 hours. At this time, the mixture was cooled to roomtemperature, filtered through diatomaceous earth and the solvent removedin vacuo. The concentrate was solvated in 400 mL methylene chloride,washed successively with water (100 mL) and brine (100 mL), dried oversodium sulfate and concentrated in vacuo to give the title compound(crude: 710 mg).

Step 3.1C2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-(3-methyl-2,5-dioxoimidazolidin-1-yl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (53 mg in 2 mL dry methylene chloride) at 0° C.was added phosgene (0.077 mL of a 1.93 M solution in toluene) followedby 0.016 mL of pyridine and the mixture stirred for 1 hour at 0° C. Atthis time, 70 mg of sarcosine methyl ester hydrochloride was added andthe mixture allowed to warm to room temperature. After 20 hours, themixture was diluted with ethyl acetate (15 mL) and the reaction quenchedby the addition of 10% citric acid. The organic portion was concentratedin vacuo to provide the crude title compound.

Step 3.1D3-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-4-(2-piperidin-2-yl-ethoxy)-1,2-dihydroquinolin-6-yl]-1-methylimidazolidine-2,4-dione

To a solution of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-(3-methyl-2,5-dioxoimidazolidin-1-yl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester in 2.0 dry methylene chloride was added a fewdrops of anisole followed by 1.0 mL of trifluoroacetic acid and themixture stirred at room temperature. After 1 hour the solvents wereremoved in vacuo and the resulting residue purified by flashchromatography on silica gel (methylene chloride:ammoniumhydroxide:methanol, 96:1:3) to give the title compound.

EXAMPLE 3.2 ##STR54##7-chloro-3-(3,5-dimethylphenyl)-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-4-(2-piperidin-2-yl-ethoxy)-1H-quinolin-2-one

Step 3.2A 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-nitro-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid 2-trimethylsilanylethyl ester

To a solution of7-chloro-3-(3,5-dimethylphenyl)-6-nitro-4-(2-piperidin-2-yl-ethoxy)-1H-quinolin-2-one(200 mg in 5 mL dicloroethane) was added 136 mg of2-(trimethylsilyl)ethyl 4-nitrophenyl carbonate followed by 0.092 mLdiisopropylethylamine and the mixture heated to reflux. After 20 hours,the reaction was cooled to room temperature, concentrated in vacuo andpurified by flash chromatography on silica gel (ethyl acetate:hexane,1:1) to give the title compound (183 mg.)

Step 3.2B2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid 2-trimethylsilanylethyl ester

Prepared essentially as described in EXAMPLE 3.1 StepB, starting from2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-nitro-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid 2-trimethylsilanylethyl ester (183 mg) to give the title compound(173 mg).

Step 3.2C2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(5-oxo-4,5-dihydro-tetrazol-1-yl)-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid 2-trimethylsilanylethyl ester

To a solution of2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid 2-trimethylsilanylethyl ester (173 mg in 5 mL dry methylenechloride) at 0° C. was added triphosgene (36 mg) followed by 0.073 mL ofpyridine and the mixture stirred for 2 hour at 0° C. At this time thereaction was quenched by the addition water, washed with brine, driedover sodium sulfate and concentrated in vacuo to give the crudeisocyante. This was solvated in 2 mL methylene chloride and added bycannula to a freshly prepared solution of aluminum azide (0.6 mmols in 5mL tetrahydrofuran) and the resulting mixture heated to reflux on an oilbath. After 20 hours, the mixture was added to 10 mL of an iced, 1Mpotassium tartarate solution and stirred for 20 minutes. This was thendiluted with water and extracted with ethyl acetate. The organic portionwas washed successively with 1 M potassium tartarate, saturated ammoniumchloride, water and brine, then dried over sodium sulfate. Purificationof the concentrate by flash chromatography on silica gel (chloroform:10%acetic acid in methanol, 97:3) gave the title compound (160 mg).

Step 3.2D2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid 2-trimethylsilanylethyl ester

To a solution of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(5-oxo-4,5-dihydro-tetrazol-1-yl)-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid2-trimethylsilanylethyl ester (35 mg in 2 mL dry N,N-dimethylformamide)was added 26 mg of finely powdered potassium carbonate followed by 0.011mL iodomethane and the mixture stirred at room temperature. After 30minutes, the reaction was quenched by the addition of saturated ammoniumchloride and the mixture partitioned between ethyl acetate and water.The organic layer was isolated and washed with water and brine, thendried over sodium sulfate. Purification of the concentrate bypreparative tlc on silica gel (hexane:ethyl acetate, 3:2) gave the titlecompound (21 mg).

Step 3.2E7-chloro-3-(3,5-dimethylphenyl)-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-4-(2-piperidin-2-yl-ethoxy)-1H-quinolin-2-one

Prepared essentially as described in EXAMPLE 3.1, Step D starting from2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid 2-trimethylsilanylethyl ester (21 mg) to give the title compound(15 mg). MASS: 509 (M+H)

EXAMPLE 3.3 ##STR55##7-chloro-3-(3,5-dimethylphenyl)-6-(2-oxo-3-pyrazin-2-yl-2,3-dihydro-imidazol-1-yl)-4-(2-piperidin-2-yl-ethoxy)-1H-quinolin-2-one

Step 3.3A2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-isocyanato-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid 2-trimethylsilanyl-ethyl ester

To a solution of2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid 2-trimethylsilanylethyl ester (from EXAMPLE 3.2B, 90 mg in amixture of 1 mL chloroform and 1 mL water containing 47 mg calciumcarbonate) at 0° C. was added 46 mg triphosgene and the mixture allowedto warm slowly to room temperature. After 2 hours, the reaction wasquenched by the addition of 2N hydrochloric acid, extracted withmethylene chloride and the organics dried over sodium sulfate to givethe crude title compound (94 mg).

Step 3.3B2-{2-[7-chloro-6-[3-(2,2-dimethoxyethyl)-3-pyrazin-2-yl-ureido]-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid 2-trimethylsilanylethyl ester

To a solution of (2,2-dimethoxyethyl)-pyrazin-2-yl-amine (103 mg in 3 mLdry tetrahydrofuran) at -78° C. was added 0.23 mL of a 2.5M solution ofbutyllithium and the mixture stirred for 30 minutes. At this time, asolution of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-isocyanato-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid 2-trimethylsilanylethyl ester (94 mg in 2 mL tetrahydrofuran) wasadded via cannula and the mixture warmed to room temperature. After 20hours, the reaction was quenched by the addition of saturated ammoniumchloride and extracted with chloroform. The organic portion was washedwith brine, dried over sodium sulfate and concentrated in vacuo.Purification of the residue by preparative tlc on silica gel (ethylacetate) gave the title compound (11 mg).

Step 3.3C7-chloro-3-(3.5-dimethylphenyl)-6-(2-oxo-3-pyrazin-2-yl-2,3-dihydro-imidazol-1-yl)-4-(2-piperidin-2-yl-ethoxy)-1H-quinolin-2-one

To a solution of2-{2-[7-chloro-6-[3-(2,2-dimethoxyethyl)-3-pyrazin-2-yl-ureido]-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid 2-trimethylsilanylethyl ester (11 mg in 2 mL chloroform) was addedaqueous trifluoroacetic acid and the mixture heated to reflux on an oilbath. After 8 hours, the reaction mixture was concentrated in vacuo andthe residue purified by preparative tic on silica gel(chloroform:methanol, 9:1) to give the title compound (4.7 mg). MASS:571 (M+H)

PREPARATION OF SYNTHETIC INTERMEDIATES(2,2-dimethoxyethyl)-pyrazin-2-yl-amine

To a solution of 2-chloropiperazine (1.0 g in 5 mL dry toluene) wasadded 2,2-dimethoxyethylamine (1.1 g) followed by 1.2 mL triethylamineand the mixture heated to reflux on an oil bath. After 48 hours, thereaction mixture was applied to a flash chromatography column (silicagel) for purification (ethyl acetate:hexane, 7:3; then 100:0) to givethe title compound (101 mg).

EXAMPLE 3.4 ##STR56##7-chloro-3-(3,5-dimethylphenyl)-6-(2-methylsulfanylimidazol-1-yl)-4-(2-piperidin-2-yl-ethoxy)-1H-quinolin-2-one

Step 3.4A2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-isothiocyanato-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a stirred suspension of calcium carbonate (320 mg) and thiophosgene(120 mg) in 10 mL water:chloroform (1:1) at 0° C. was added2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (450 mg, prepared essentially as described inExample 1) and the mixture stirred at low temperature. After 2 hours thereaction was quenched by the addition of 10% hydrochloric acid andstirring continued until the gas evolution ceased. The mixture was thenextracted with chloroform, the combined organics dried over magnesiumsulfate and concentrated in vacuo to provide the crude title compound(480 mg).

Step 3.4B2-(2-{7-chloro-3-(3,5-dimethylphenyl)-6-[3-(2-ethoxy-3-methoxypropyl)-thioureido]-2-oxo-1,2-dihydro-quinolin-4-yloxy}-ethyl)-piperidine-1-carboxylicacid tert-butyl ester

To a solution of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-isothiocyanato-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (480 mg in 15 mL dry toluene) was added 130 mg of2,2-diethoxy-ethylamine and the mixture stirred at room temperature for30 minutes, then heated to reflux on an oil bath. After 2 hours themixture was cooled to room temperature, concentrated in vacuo and theresidue washed with diethyl ether. Collection of the solids gave thecrude title compound (410 mg).

Step 3.4C7-chloro-3-(3.5-dimethylphenyl)-6-(2-methylsulfanylimidazol-1-yl)-4-(2-piperidin-2-yl-ethoxy)-1H-quinolin-2-one

A solution of2-(2-{7-chloro-3-(3,5-dimethylphenyl)-6-[3-(2-ethoxy-3-methoxypropyl)-thioureido]-2-oxo-1,2-dihydro-quinolin-4-yloxy}-ethyl)-piperidine-1-carboxylicacid tert-butyl ester (410 mg in 20 mL 30% sulfuric acid) was heated toreflux on an oil bath. After 20 hours, the reaction was cooled to roomtemperature and washed with methylene chloride. The aqueous portion wasneutralized by the addition of sodium hydroxide and the mixture thenconcentrated in vacuo. Purification of the residue by flashchromatography on silica gel (ethyl acetate; then chloroform:1% ammoniain methanol, 9:1) gave the title compound (150 mg).

Following a procedure similar to that described above, the followingcompounds were prepared:

    ______________________________________                                          #STR57##                                                                    Ex. #   R.sub.6              m/e                                              ______________________________________                                          3A                                                                                                         523 (M #                                                                    + H)                                                - 3B                                                                                                      535 (M + H)                                       - 3C                                                                                                      577 (M + H)                                       - 3D                                                                                                      535 (M + H)                                       - 3E                                                                                                      495 (M + H)                                       - 3F                                                                                                      523 (M + H)                                       - 3G                                                                                                      537 (M + H)                                       - 3H                                                                                                      551 (M + H)                                       - 3I                                                                                                      551 (M + H)                                       - 3J                                                                                                      537 (M + H)                                       - 3K                                                                                                      585 (M + H)                                       - 3L                                                                                                      587 (M + H)                                    ______________________________________                                    

EXAMPLE 4.1 ##STR70##7-chloro-3-(3,5-dimethylphenyl)-4-(2-piperidin-2-yl-ethoxy)-6-(pyrrolidine-1-carbonyl)-1H-quinolin-2-one

Step 4.1A 2-amino-4-chloro-5-iodobenzoic acid methyl ester

To a suspension of 2-acetylamino-4-chlorobenzoic acid methyl ester (2.0g in 80 mL of dry chloroform) and 2.5 g silver trifluoromethanesulfonatewas added iodine (2.87 g in 40 mL chloroform) and the mixture stirred atroom temperature. After 5 hours, the mixture was filtered overdiatomaceous earth and the filtrate concentrated in vacuo. Purificationof the resulting oil by flash chromatography on silica gel (hexane:ethylacetate, 95:5; then 90:10) gave the title compound (2.26 g).

Step 4.1B 4-chloro-2-[2-(3,5-dimethylphenyl)-acetylamino]-5-iodo-benzoicacid methyl ester

To a solution of 2-amino-4-chloro-5-iodobenzoic acid methyl ester (2.26g in 25 mL dichloroethane) was added (3,5-dimethylphenyl) acetylchloride (1.2 g in 15 mL dichloroethane) and the mixture heated to 75°C. on an oil bath. After 3 hours, the reaction was cooled and thesolvent removed in vacuo. The title compound was isolated bycrystallization from methanol (2.7 g).

Step 4.1C5-allyl-4-chloro-2-[2-(3,5-dimethylphenyl)-acetylamino]-benzoic acidmethyl ester

To a suspension of4-chloro-2-[2-(3,5-dimethylphenyl)-acetylamino]-5-iodo-benzoic acidmethyl ester (2.39 g in 12 mL N,N-dimethylformamide) and 0.183 gbis(triphenylphosphine)palladium(II) chloride was added 2.02 mL allyltinand the mixture heated to 100° C. on an oil bath. After 2 hours, themixture was cooled, partitioned between ethyl acetate and water and theorganic layer washed further with brine. Concentration of the dried(magnesium sulfate) organics and purification by flash chromatography onsilica gel (hexane:ethyl acetate, 95:5; then 90:10) gave the titlecompound (1.4 g).

Step 4.1D 6-allyl-7-chloro-3-(35-dimethylphenyl)-4-hydroxy-1H-quinolin-2-one

To a solution of5-allyl-4-chloro-2-[2-(3,5-dimethylphenyl)-acetylamino]-benzoic acidmethyl ester (1.4 g in 40 mL dry tetrahydrofuran) at 0° C. was addeddropwise a solution of sodium bis(trimethylsilyl)amide (9.8 mL of a 1.0Msolution in tetrahydrofuran) and the mixture warmed to room temperature.After 4 hours, the reaction was cooled to 0° C. and quenched by theaddition of of 200 mL iced 6N hydrochloric acid. The slurry was stirredfor 15 minutes then filtered and washed sequentially with ice water (500mL), cold hexane (200 mL) and cold toluene (100 mL). The residue wasdried in vacuo to give the title compound (960 mg).

Step 4.1E2-{2-[6-allyl-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of6-allyl-7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-1H-quinolin-2-one (960mg in 30 mL of tetrahydrofuran) at 0° C. was added 615 mg of2-(2-hydroxyethyl)-piperidine-1-carboxylic acid tert-butyl ester and1.04 g of triphenylphosphine followed by 0.56 mL of diethylazodicarboxylate and the mixture warmed to room temperature. After 20hours, the solvents were removed in vacuo and the residue purified byflash chromatography on silica gel (hexane:ethylacetate, 85:15; then80:20; then 90:10) to give the title compound (1.19 g).

Step 4.1F4-[2-(1-tert-butoxycarbonyl-piperidin-2-yl)-ethoxy]-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydro-quinoline-6-carboxylicacid

To a solution of2-{2-[6-allyl-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (517 mg in 35 mL of a mixture oftert-butanol:tetrahydrofuran:water, 10:3:1) was added 121 mg4-methylmorpholine N-oxide and 48 mg osmium tetraoxide and the mixturestirred at room temperature. After 2 hours, the reaction was dilutedwith 7.5 mL of water followed by the addition sodium periodate (602 mg)and sodium bicarbonate (946 mg) and the resulting suspension stirredrapidly for 90 minutes. The mixture was then filtered over diatomaceousearth and extracted with ethyl acetate. Concentration of the organics invacuo provided the crude aldehyde product which was used in thefollowing reaction without purification.

The crude product was solvated in 15 mL tert-butanol followed by theaddition of sodium phosphate (8 mL of a 1.25 M aqueous solution) andpotassium permanganate (15 mL of a 1 M aqueous solution) and the mixturestirred at room temperature. After 2 hours, the reaction was quenched bythe addition of sodium sulfite, extracted with ethyl acetate, and theaqueous layer adjusted to pH3 with 1 N hydrochloric acid. The aqueousportion was extracted with ethyl acetate and the organics dried overmagnesium sulfate. Purification of the concentrate by flashchromatography on silica gel (hexane:ethyl acetate, 7:3+1% acetic acid)provided the title compound (150 mg).

Step 4.1G2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(pyrrolidine-1-carbonyl)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of4-[2-(1-tert-butoxycarbonyl-piperidin-2-yl)-ethoxy]-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydro-quinoline-6-carboxylicacid (15 mg in 0.6 mL of dry methylene chloride) was added 8.0 mg of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)followed by 6.0 mg 1-hydroxybenzotriazole (HOBt) and the mixture stirredfor 10 minutes. At this time, 9.4 mg of pyrrolidine and the reactionallowed to proceed at room temperature. After 4 hours, the mixture wasconcentrated in vacuo and purified by flash chromatography on silica gel(methylene chloride:10% ammonium hydroxide in methanol, 95:5) to givethe tilte compound (8 mg).

Step 4.1H7-chloro-3-(3.5-dimethylphenyl)-4-(2-piperidin-2-yl-ethoxy)-6-(pyrrolidine-1-carbonyl)-1H-quinolin-2-one

To a solution of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(pyrrolidine-1-carbonyl)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (8.0 mg in 2.0 dry methylene chloride) was added afew drops of anisole followed by 1.0 mL of trifluoroacetic acid and themixture stirred at room temperature. After 30 minutes the solvents wereremoved in vacuo and the resulting residue purified by flashchromatography on silica gel (methylene chloride: 10% ammonium hydroxidein methanol, 95:5; then 90:10) to give the title compound (5 mg).

EXAMPLE 4.2 ##STR71##7-chloro-3-(3,5-dimethylphenyl)-2-oxo-4-(2-piperidin-2-yl-ethoxy)-1,2-dihydroquinoline-6-carboxylicacid pyrimidin-4-ylamide

Step 4.2A7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-6-iodo-1H-quinolin-2-one

To a solution of4-chloro-2-[2-(3,5-dimethylphenyl)-acetylamino]-5-iodo-benzoic acidmethyl ester (EXAMPLE 4.1B, 10.9 g in 180 mL dry tetrahydrofuran) at 0°C. was added dropwise 59.5 mL of a 1 M solution of sodiumbis(trimethylsilyl)amide in tetrahydrofuran and the mixture allowed towarm to room temperature. After 1.5 hours, the mixture was cooled to 0°C. and the reaction quenched by the addition of 400 mL ice:6Nhydrochloric acid (1:1). This was stirred for 15 minutes then filteredto collect the solid product. The solids were washed with ice-water thencold acetonitrile and dried to give the title compound (9.8 g).

Step 4.2B2-{2-[7-chloro-3-(3.5-dimethylphenyl)-6-iodo-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of 2-(2-hydroxyethyl)-piperidine-1-carboxylic acidtert-butyl ester (10 g in 450 mL dry tetrahydrofuran) was added 22.3 gof 7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-6-iodo-1H-quinolin-2-onefollowed by 13.7 g of triphenylphosphine and the mixture stirred at roomtemperature. To this was added 8.2 mL of diethyl azodicarboxylate (DEAD)and stirring was continued for 72 hours. At this time the solvents wereremoved to a minimum volume in vacuo and the mixture filterd through asilica gel pad to remove the phosphine by-products. The filtrate wasconcentrated in vacuo to provide the partially purified title compound(17.5 g).

Step 4.2C2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(pyrimidin-4-ylcarbamoyl)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a suspension of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-iodo-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acidtert-butyl ester (0.10 g in a mixture of 1 mL N,N-dimethylformamide and0.04 mL triethylamine) was added 75 mg of 4-aminopyrimidine followed by0.8 mg dichlorobis(triphenylphosphine)palladium(II) and the flaskflushed (5×) with carbon monoxide. The mixture was then heated to 90° C.on an oil bath under a carbon monoxide atmosphere. After 16 hours, themixture was cooled to room temperature, diluted with ethyl acetate andwashed with water and brine. The organic portion was dried over sodiumsulfate and concentrated in vacuo. Purification by flash chromatographyon silica gel (ethyl acetate:hexane, 35:65; then methylenechloride:methanol, 95:5) gave the title compound (70 mg).

Step 4.2D7-chloro-3-(3,5-dimethylphenyl)-2-oxo-4-(2-piperidin-2-yl-ethoxy)-1,2-dihydroquinoline-6-carboxylicacid pyrimidin-4-ylamide

Prepared essentially as described in EXAMPLE 5, Step B from 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(pyrimidin-4-ylcarbamoyl)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester. MASS: 532 (M+H)

Following a procedure similar to that described above, the followingcompounds were prepared:

    ______________________________________                                          #STR72##                                                                    Ex. # R.sub.6                 m/e                                             ______________________________________                                          4A                                                                                                          537 (M #                                                                    + H)                                               - 4B                                                                                                       545 (M + H)                                      - 4C                                                                                                       523 (M + H)                                      - 4D                                                                                                       565 (M + H)                                      - 4E                                                                                                       531 (M + H)                                      - 4F                                                                                                       532 (M + H)                                      - 4G                                                                                                       521 (M + H)                                      - 4H                                                                                                       535 (M + H)                                      - 4I                                                                                                       588 (M + H)                                      - 4J                                                                                                       561 (M + H)                                      - 4K                                                                                                       552 (M + H)                                      - 4L                                                                                                       531 (M + H)                                      - 4M                                                                                                       531 (M + H)                                      - 4N                                                                                                       532 (M + H)                                      - 4O                                                                                                       532 (M + H)                                      - 4P                                                                                                       521 (M + H)                                      - 4Q                                                                                                       538 (M + H)                                      - 4R                                                                                                       538 (M + H)                                      - 4S                                                                                                       560 (M + H)                                      - 4T                                                                                                       538 (M + H)                                      - 4U                                                                                                       548 (M + H)                                      - 4V                                                                                                       #STR94##                                         - 4W                                                                                                       566 (M + H)                                      - 4X                                                                                                       546 (M + H)                                      - 4Y                                                                                                       546 (M + H)                                      - 4Z                                                                                                       557 (M + H)                                      - 4AA                                                                                                      #STR99##                                         - 4BB                                                                                                      572 (M + H)                                      - 4CC                                                                                                      666 (M + H)                                      - 4DD                                                                                                      534 (M + H)                                      - 4EE                                                                                                      608 (M + H)                                      - 4FF                                                                                                      #STR104##                                        - 4GG                                                                                                      #STR105##                                        - 4HH                                                                                                      535 (M + H)                                      - 4II                                                                                                      551 (M + H)                                      - 4JJ                                                                                                      534 (M + H)                                      - 4KK                                                                                                      #STR109##                                        - 4LL                                                                                                      630 (M + H)                                      - 4MM                                                                                                      574 (M + H)                                      - 4NN                                                                                                      537 (M + H)                                   ______________________________________                                    

EXAMPLE 5 ##STR113## Thiophene-2-sulfonic acid [7 -chloro-3-(3,5-dimethylphenyl)-2-oxo-4-(2-piperidin-2-yl-ethoxy)-1,2-dihydroquinolin-6-yl]-amide

Step 5A2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(thiophene-2-sulfonylamino)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (prepared essentially as described in Example 1,200 mg in 10 mL pyridine) was added a catalytic amount ofN,N-dimethylaminopyridine followed by 139 mg 2-thiophenesulfonylchloride and the mixture stirred at room temperature. After 30 minutes,the reaction was quenched by the addition of saturated aqueous sodiumbicarbonate, extracted with ethyl acetate and dried over sodium sulfate.Concentration in vacuo gave the crude title compound.

Step 5B Thiophene-2-sulfonic acid[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-4-(2-piperidin-2-yl-ethoxy)-1,2-dihydroquinolin-6-yl]-amide

To a solution of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(thiophene-2-sulfonylamino)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester in 5 mL methylene chloride was added a few dropsof anisole followed by 1.0 mL of trifluoroacetic acid and the mixturestirred at room temperature. After 30 minutes the solvents were removedin vacuo and the resulting residue purified by flash chromatography onsilica gel (methylene chloride:10% ammonium hydroxide in methanol, 95:5;then 90:10) to give the title compound.

EXAMPLE 6.1 ##STR114##7-chloro-3-(3,5-dimethylphenyl)-6-(3-oxo-3-pyrrolidin- 1-yl-propyl)-4-(2-piperidin-2-yl-ethoxy)-1H-quinolin-2-one

Step 6.1A2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-(3-hydroxy-propyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester

To a solution of2-{2-[6-allyl-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (Example 4, Step 4E: 400 mg in 7.0 mL of drytetrahydrofuran) at 0° C. was added 2.18 mL of a 1M solution of boranein tetrahydrofuran dropwise over 10 minutes. After 3 hours, the reactionwas treated sequentially with sodium hydroxide (0.84 mL of a 3Msolution) and hydrogen peroxide (0.29 mL of a 30% solution) and themixture allowed to warm to room temperature. After 2 hours the mixturewas extracted with ethyl acetate, washed with brine and dried oversodium sulfate. Purification of the concentrate by flash chromatographyon silica gel (hexane:ethyl acetate, 8:2; then 7:3; then 3:2; then 1:1)gave the title compound (253 mg).

Step 6.1B 2-{2-[6-(2-carboxyethyl)-7-chloro-3-(35-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-(3-hydroxy-propyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (176 mg in 3.0 mL methylene chloride) was added 20mg powdered 4Å sieves, 73 mg of 4-methylmorpholine-N-oxide, followed by11 mg tetrapropylammonium perruthenate(VII) and the mixture stirred atroom temperature. After 3 hours, the solvent was removed in vacuo andthe crude aldehyde product resolvated in a mixture of tert-butanol (2mL) and sodium phosphate (1 mL of a 1.25M solution). To this was added1.86 mL of a 1M aqueous solution of potassium permanganate. After 30minutes, the mixture was extracted with ethyl acetate, dried over sodiumsulfate and purified by flash chromatography on silica gel (hexane:ethylacetate, 1:1; then methylene chloride:methanol, 90:10) to give the titlecompound (107 mg).

Step 6.1C2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(3-oxo-3-pyrrolidin-1-yl-propyl)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of2-{2-[6-(2-carboxyethyl)-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (15 mg in 0.5 mL of dry methylene chloride) wasadded 8.0 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC) followed by 5.2 mg 1-hydroxybenzotriazole (HOBt) andthe mixture stirred for 10 minutes. At this time, 9.2 mg of pyrrolidinewas added and the reaction allowed to proceed at room temperature. After40 minutes, the mixture was concentrated in vacuo and purified by flashchromatography on silica gel (methylene chloride: 10% ammonium hydroxidein methanol, 95:5; then 90:10) to give the title compound (9 mg).

Step 6.1D7-chloro-3-(3,5-dimethylphenyl)-6-(3-oxo-3-pyrrolidin-1-yl-propyl)-4-(2-piperidin-2-yl-ethoxy)-1H-quinolin-2-one

To a solution of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(3-oxo-3-pyrrolidin-1-yl-propyl)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (9.0 mg in 2.0 dry methylene chloride) was added afew drops of anisole followed by 1.0 mL of trifluoroacetic acid and themixture stirred at room temperature. After 30 minutes the solvents wereremoved in vacuo and the resulting residue purified by flashchromatography on silica gel (methylene chloride:10% ammonium hydroxidein methanol, 9:1) to give the title compound (7.0 mg). MASS: 536 (M+H)

EXAMPLE 6.2 ##STR115## 7-chloro-3-(3,5-dimethylphenyl)-4-(2-piperidin-2-yl-ethoxy)-6 (pyridine-2-carbonyl)-1H-quinolin-2-one

Step 6.2A2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(pyridine-2-carbonyl)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-iodo-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (78 mg in 1 mL N,N-dimetlylformamide) was added0.045 mg 2-tributylstannanyl-pyridine followed by 0.03 mL triethylamineand 0.002 mg dichlorobis(triphenylphosphine)palladium(II) and the flaskflushed (5×) with carbon monoxide. The mixture was then heated to 90° C.on an oil bath under a carbon monoxide atmosphere. After 16 hours, themixture was cooled to room temperature, diluted with ethyl acetate andwashed with water and brine. The organic portion was dried over sodiumsulfate and concentrated in vacuo. Purification by flash chromatographyon silica gel (ethyl acetate:hexane, 35:65; then chloroform:methanol,95:5) gave the title compound (14 mg).

Step 6.2B7-chloro-3-(3,5-dimethylphenyl)-4-(2-piperidin-2-yl-ethoxy)-6-(pyridine-2-carbonyl)-1H-quinolin-2-one

The title compound was prepared essentially as described in EXAMPLE 5,Step B from 14 mg of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(pyridine-2-carbonyl)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester to give 12 mg of product. MASS: 516 (M+H)

EXAMPLE 6.3 ##STR116##7-chloro-3-(3,5-dimethylphenyl)-4-(2-piperidin-2-yl-ethoxy)-6-(9H-purin-8-ylamino)-1H-quinolin-2-one

Step 6.3A2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(9H-purin-8-ylamino)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-isothiocyanato-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (210 mg in 5 mL toluene) was added 250 mgmercury(II) oxide followed by 130 mg 4,5-diaminopyrimidine and themixture heated to reflux on an oil bath. After 48 hours, the mixture wascooled to room temperature and the reaction quenched by the addition of2N hydrochloric acid (4 mL). The solvents were removed in vacuo and theresidue treated with 2N ammonia in methanol (10 mL) then concentratedonce again. The residue was washed with chloroform and the solidsremoved by filtration. Concentration of the organics and purification byflash chromatography on silica gel (ethyl acetate:hexane, 1:1; thenchloroform:2N ammonia in methanol, 9:1) gave the title compound (10 mg).

Step 6.3B7-chloro-3-(3,5-dimethylphenyl)-4-(2-piperidin-2-yl-ethoxy)-6-(9H-purin-8-ylamino)-1H-quinolin-2-one

The title compound was prepared essentially as described in EXAMPLE 5,Step B from 10 mg of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(9H-purin-8-ylamino)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester to give the final product (6 mg). MASS: 544 (M+H)

EXAMPLE 6.4 ##STR117##7-chloro-3-(3,5-dimethylphenyl)-4-(2-piperidin-2-yl-ethoxy)-6-(pyrazin-2-ylamino)-1H-quinolin-2-one

Step 6.4A2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(pyrazin-2-ylamino)-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a suspension of2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (prepared essentially as described in Example 1,100 mg in 1 mL chloropyrazine) was added 500 mg zinc bromide and themixture heated to 150° C. on an oil bath. After 3 hours, the mixture wascooled to room temperature, diluted with ethyl acetate and filteredthrough diatomaceous earth. The volatile organics were removed in vacuoand the residue dissolved in ethyl acetate, washed with water and theorganic portion dried over sodium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane,1:1) to give the title compound (12 mg).

Step 6.4B 7-chloro-3 -(3,5-dimethylphenyl)-4-(2-piperidin-2-yl-ethoxy)-6-(pyrazin-2-ylamino)-1H-quinolin-2-one

The title compound was prepared essentially as described in EXAMPLE 5,Step B from 12 mg of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(pyrazin-2-ylamino)-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester to give the final product (8 mg). MASS: 504 (M+H)

EXAMPLE 6.5 ##STR118##7-chloro-3-(3,5-dimethylphenyl)-4-(2-piperidin-2-yl-ethoxy)-6-pyrazin-2-ylethynyl-1H-quinolin-2-one

Step 6.5A2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-ethynyl-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a suspension of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-iodo-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acidtert-butyl ester (EXAMPLE 4.2 Step B, 200 mg in 3 mLN,N-dimethylformamide) was added tetrakis(triphenylphosphine)palladium(18 mg) followed by copper(I) iodide (30 mg), n-propylamine (0.26 mL)and trimethylsilylacetylene (0.45 mL) and the mixture sealed in athick-walled tube. This was heated to 95° C. on an oil bath for 10hours, then cooled to room temperature and diluted with diethyl ether.This was washed successively with water and brine and the combinedorganics dried over magnesium sulfate. Purification of the concentrateby flash chromatography on silica gel (ethyl acetate:hexane, 30:70; then40:60) gave a mixture of the title compound and the correspondingtrimethylsilyl derivative (155 mg). This material was converted to thetitle compound by treatment with 4.4 mg of potassium carbonate in 2 mLmethanol. After 1 hour, the mixture was diluted with methylene chloride,washed with half-saturated sodium chloride, then brine and dried overmagnesium sulfate. Purification of the concentrate by flashchromatography on silica gel (ethyl acetate:hexane, 30:70; then 40:60)gave the title compound (127 mg).

Step 6.5B2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-pyrazin-2-ylethynyl-1,2-dihydroquinolin4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-ethynyl-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (123 mg in 1.5 mL N,N-dimethylformamide) was addedtetrakis(triphenylphosphine)palladium (13 mg) followed by copper(I)iodide (22 mg), n-propylamine (0.19 mL) and chloropyrazine (0.026 mL)and the mixture heated to 90° C. on an oil bath. After 10 minutes, themixture was cooled to room temperature, diluted with diethyl ether andwashed successively with water and brine then dried over magnesiumsulfate. Purification of the concentrate by flash chromatography onsilica gel (ethyl acetate:hexane, 30:70; then 40:60; then 50:50) gavethe title compound (69 mg).

Step 6.5C7-chloro-3-(3,5-dimethylphenyl)-4-(2-piperidin-2-yl-ethoxy)-6-pyrazin-2-ylethynyl-1H-quinolin-2-one

The title compound was prepared essentially as described in EXAMPLE 5,Step B from 22 mg of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-pyrazin-2-ylethynyl-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester to give the final product (18 mg). MASS 513 (M+H)

EXAMPLE 6.6 ##STR119##7-chloro-3-(3,5-dimethylphenyl)-4-(2-piperidin-2-yl-ethoxy)-6-(pyrimidin-4-ylaminomethyl)-1H-quinolin-2-one

Step 6.6A2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-(methoxy-methylcarbamoyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of N,O-dimethylhydroxylamine (1.14 g in 50 mL drymethylene chloride) was added 1.5 mL triethylamine followed by 4-[2-(1-tert-butoxycarbonylpiperidin-2-yl)-ethoxy]-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinoline-6-carboxylicacid (EXAMPLE 4.1, Step F, 1.35 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 1.35g) and 4-dimethylaminopyridine (400 mg) and the mixture stirred at roomtemperature. After 36 hours, the mixture was concentrated in vacuo andthe residue purified by flash chromatography on silica gel (ethylacetate) to give the title compound (1.18 g).

Step 6.6B2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-formyl-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-(methoxy-methylcarbamoyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (1.18 g in dry tetrahydrofuran) was added 3.9 mLof a 1M solution of lithium aluminum hydride and the mixture stirred atroom temperature. After 2 hours, the reaction was quenched by theaddition of saturated ammonium chloride solution. The mixture wasfiltered through diatomaceous earth and the filtrate extracted withethyl acetate. The organics were then dried over magnesium sulfate andconcentrated in vacuo to give the crude title compound (900 mg).

Step 6.6C 2-{2-[7-chloro-3-(35-dimethylphenyl)-2-oxo-6-(pyrimidin-4-yliminomethyl)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl

To a solution of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-formyl-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (360 mg in 150 mL toluene) was added benzotriazole(79 mg) followed by 4-aminopyrimidine (129 mg) and a catalytic amount ofp-toluenesulfonic acid. The flask was fitted with a Dean-Stark trap andthe mixture heated to reflux on an oil bath. After 20 hours, the mixturewas cooled to room temperature and the volatile organics removed invacuo. The residue was dissolved in chloroform then washed with 2Nsodium hydroxide. The organic portion was dried over magnesium sulfate,concentrated in vacuo and purified by flash chromatography on silica gel(ethyl acetate:hexane, 3:2) to give the title compound (300 mg).

Step 6.6D2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(pyrimidin-4-ylaminomethyl)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(pyrimidin-4-yliminomethyl)-1,2-dihydroquinolin-4-yloxy]-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (36 mg in 2 mL drytetrahydrofuran) at -10° C. was added a 1M solution of lithium aluminumhydride (2 mL) and the mixture stirred at low temperature. After 2hours, the reaction was quenched by the addition of water, filtered andthe organic portion concentrated in vacuo. Purification by preparativetic on silica gel gave the title compound.(12 mg).

Step 6.6E7-chloro-3-(3,5-dimethylphenyl)-4-(2-piperidin-2-yl-ethoxy)-6-(pyrimidin-4-ylaminomethyl)-1H-quinolin-2-one

The title compound was prepared essentially as described in EXAMPLE 5,Step B from 12 mg of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(pyrimidin-4-ylaminomethyl)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester to give the final product (6 mg). MASS: 518 (M+H)

Following a procedure similar to that described above, the followingcompounds were prepared:

    ______________________________________                                          #STR120##                                                                   Ex. # R.sub.6                 m/e                                             ______________________________________                                          6A                                                                                                          573 (M ##                                                                   + H)                                               - 6B                                                                                                       531 (M + H)                                      - 6C                                                                                                       533 (M + H)                                      - 6D                                                                                                       #STR124##                                        - 6E                                                                                                       546 (M + H)                                      - 6F                                                                                                       551 (M + H)                                      - 6G                                                                                                       491 (M + H)                                      - 6H                                                                                                       551 (M + H)                                      - 6I                                                                                                       570 (M + H)                                      - 6J                                                                                                       505 (M + H)                                      - 6K                                                                                                       507 (M + H)                                      - 6L                                                                                                       535 (M + H)                                      - 6M                                                                                                       535 (M + H)                                      - 6N                                                                                                       566 (M + H)                                      - 6O                                                                                                       535 (M + H)                                      - 6P                                                                                                       546 (M + H)                                      - 6Q                                                                                                       546 (M + H)                                      - 6R                                                                                                       581 (M + H)                                      - 6S                                                                                                       560 (M + H)                                      - 6T                                                                                                       #STR140##                                        - 6U                                                                                                       512 (M + H)                                   ______________________________________                                    

EXAMPLE 7.1 ##STR142##7-chloro-3-(3,5-dimethylphenyl)-4-(2-piperidin-2-yl-ethoxy)-6-pyridin-2-yl-1H-quinolin-2-one

Step 7.1A2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-pyridin-2-yl-1,2-dihydroquinolin-4-yloxy]-ethyl}1-piperidine-1-carboxylicacid tert-butyl ester

To a solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-iodo-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (EXAMPLE 4.2 Step B, 150 mg in 3 mL dry toluene)was added 104 mg of 2-tributylstannanylpyridine followed by 50 mglithium chloride. To this, 8 mg of dichlorobis(triphenylphosphine)palladium (II) was added and the mixture heated to reflux on an oilbath. After 24 hours, the mixture was cooled to room temperature anddiluted with 5 mL ethyl acetate/5 mL water. The aqueous layer wassaturated with potassium fluoride and stirred vigorously for 15 minutes.The organic layer was isolated and washed with water and brine thendried over magnesium sulfate. Purification of the concentrate by flashchromatography on silica gel (ethyl acetate:hexane, 3:2) gave the titlecompound (140 mg).

Step 7.1B7-chloro-3-(3,5-dimethylphenyl)-4-(2-piperidin-2-yl-ethoxy)-6-pyridin-2-yl-1H-quinolin-2-one

To a solution of2-(2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-pyridin-2-yl-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester in 2.0 dry methylene chloride was added a fewdrops of anisole followed by 2.0 mL of trifluoroacetic acid and themixture stirred at room temperature. After 1.5 hours, the solvents wereremoved in vacuo and the resulting residue purified by reverse-phasemplc (C-8, methanol:0.1% aqueous trifluoroacetic acid, 55:45) to givethe title compound (112 mg). MASS: 488 (M+H)

EXAMPLE 7.2 ##STR143##7-chloro-3-(3,5-dimethylphenyl)-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-4-(2piperidin-2-yl-ethoxy)-1H-quinolin-2-one

Step 7.2A2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-iodo-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (EXAMPLE 4.2 Step B, 200 mg in a mixture of 3 mLdry N,N-dimethylformamide and 0.9 mL triethylamine) was added 118 mg ofacetamide oxime followed by 11 mg of dichlorobis(triphenylphosphine)palladium (II) and the mixture heated to reflux on an oil bath under anatmosphere of carbon monoxide. After 12 hours, the mixture was cooled toroom temperature and diluted with ethyl acetate and 0.5N hydrochloricacid. This was extracted with ethyl acetate and the organic portionwashed with brine then dried over sodium sulfate. Purification of theconcentrate by flash chromatography on silica gel (ethyl acetate:hexane,1:4; then 3:7) gave the title compound (88 mg).

Step 7.2B 7-chloro-3-(3,5-dimethylphenyl-6-(3-methyl-[12,4]oxadiazol-5-yl)-4-(2-piperidin-2-yl-ethoxy)-1H-quinolin-2-one

The title compound was prepared essentially as described in EXAMPLE 5,Step B from 81 mg of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester to give the final product (63 mg).

    ______________________________________                                        Ex. # R.sub.6                 m/e                                             ______________________________________                                          7A                                                                                                          477 (M ##                                                                   + H)                                               - 7B                                                                                                       488 (M + H)                                      - 7C                                                                                                       475 (M + H)                                      - 7D                                                                                                       488 (M + H)                                      - 7E                                                                                                       489 (M + H)                                      - 7F                                                                                                       557 (M + H)                                   ______________________________________                                    

Following a procedure similar to that described above, the followingcompounds were prepared:

    ______________________________________                                        Ex. # R.sub.6                 m/e                                             ______________________________________                                          7A                                                                                                          477 (M ##                                                                   + H)                                               - 7B                                                                                                       488 (M + H)                                      - 7C                                                                                                       475 (M + H)                                      - 7D                                                                                                       488 (M + H)                                      - 7E                                                                                                       489 (M + H)                                      - 7F                                                                                                       557 (M + H)                                   ______________________________________                                    

EXAMPLE 8 ##STR156## 7-chloro-3-(3,5-dimethylphenyl)-4-(2-piperidin-2-yl-ethoxy)-6-(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-1H-quinolin-2-one

Step 8A2-{2-[7-chloro-6-(2,3-dihydroxypropyl)-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of2-{2-[6-allyl-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (EXAMPLE 4.1 Step E, 6.0 g in a mixture of 80 mLtert-butanol, 24 mL tetrahydrofuran and 8 mL water) was added 1.4 g4-methylmorpholine N-oxide followed by 140 mg osmium tetraoxide and themixture stirred at room temperature. After 20 hours, the mixture wasconcentrated in vacuo and the residue dissolved in ethyl acetate andwashed sequentially with water and brine. The combined organics weredried over sodium sulfate and purified by flash chromatography on silicagel (ethyl acetate:hexane, 1:1; then methylene chloride:10% ammoniumhydroxide in methanol, 9:1) to give the title compound (5.7 g).

Step 8B2-{2-[6-carboxymethyl-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of-{2-[7-chloro-6-(2,3-dihydroxypropyl)-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (4.3 g in a mixture of 200 mL methanol and 3 mLpyridine) at 0° C. was added 7.4 g lead(IV) acetate in portions over 5minutes and the mixture stirred at low temperature. After 10 minutes,the reaction was quenched by the addition of sodium sulfite and themixture extracted with methylene chloride. The organic portion waswashed with brine, dried over sodium sulfite and concentrated in vacuoto give the crude aldehyde intermediate.

The aldehyde was solvated in 200 mL tert-butanol and then 24 mL of a1.25M solution of sodium dihydrogenphosphate was added followed by thedropwise addition of 44.5 mL of a 1M aqueous solution of potassiumpermanganate. After 2 hours, the reaction was quenched by the additionof saturated aqueous sodium sulfite. The pH of the solution was adjustedto 3 by the addition of IN hydrochloric acid then the mixture wasextracted with ethyl acetate, washed with brine and dried over sodiumsulfate. Purification of the concentrate by flash chromatography onsilica gel (ethyl acetate:hexane 3:7=1% acetic acid) gave the titlecompound (2.8 g).

Step 8C2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of2-{2-[6-carboxymethyl-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (57 mg in 0.60 mL dry methylene chloride) wasadded 20 mg N-hydroxy-4-methylbenzamidine followed by 30 mg1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 6mg dimethylaminopyridine and the mixture stirred at room temperature.After 6 hours, the mixture was diluted with methylene chloride, washedwith water and the organic portion concentrated in vacuo. Purificationof the concentrate by flash chromatography on silica gel (methylenechloride:methanol, 98:2; then 97:3) gave the intermediate esterderivative (61 mg). The ester was dissolved in 2.5 mL toluene and heatedto reflux on an oil bath. After 2.5 hours, the mixture was cooled toroom temperature and the concentrate purified by flash chromatography onsilica gel (ethyl acetate:hexane, 1:4; then 2:3) to give the titlecompound (51 mg).

Step 8D7-chloro-3-(3,5-dimethylphenyl)-4-(2-piperidin-2-yl-ethoxy)-6-(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-1H-quinolin-2-one

The title compound was prepared essentially as described in EXAMPLE 5,Step B from 51 mg of2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(3-p-tolyl-[1,2,4]oxadiazol-5-ylmethyl)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester to give the final product (31 mg). MASS 583 (M+H)##STR157##

Following a procedure similar to that described above, the followingcompounds were prepared:

    ______________________________________                                        Ex. #    R                 m/e                                                ______________________________________                                          8A                                                                                                       600 (M ##                                                                   + H)                                                  - 8B                                                                                                    570 (M + H)                                         - 8C                                                                                                    571 (M + H)                                         - 8D                                                                                                    569 (M + H)                                         - 8E                                                                                                    571 (M + H)                                         - 8F                                                                                                    571 (M + H)                                         - 8G                                                                                                    629 (M + H)                                         - 8H                                                                                                    583 (M + H)                                      ______________________________________                                    

EXAMPLE 9 ##STR166## (S)-pyrimidine-4-carboxylic acid{7-chloro-3-(3,5-dimethylphenyl)-4-[2-(1-methylpiperidin-2-yl)-ethoxy]-2-oxo-1,2-dihydroquinolin-6-yl}-amide

To a solution of pyrimidine-4-carboxylic acid(S)-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-4-(2-piperidin-2-yl-ethoxy)-1,2-dihydroquinolin-6-yl]-amide(prepared essentially as described in EXAMPLE 2, 9 mg in 0.40 mLmethanol) was added 6 mg paraformaldehyde followed by 20 mg powdered 4Amolecular sieves and 0.01 mL acetic acid and the mixture stirred at roomtemperature for 10 minutes. At this time, 5 mg sodium cyanoborohydridewas added and the stirring continued. After 2 hours, 0.5 mLtetrahydrofuran was added to ensure homogeneity and after 60 hours thereaction was quenched by the addition of water. The reaction mixture wasextracted with methylene chloride and the combined organics washed withbrine and dried over sodium sulfate. Purification of the concentrate byflash chromatography on silica gel (methylene chloride:10% ammoniumhydroxide in methanol, 95:5; then 92:8) gave the title compound (6.7mg). MASS: 546 (M+H) ##STR167##

Following a procedure similar to that described above, the followingcompounds were prepared:

    ______________________________________                                        Ex. # R.sub.6                  m/e                                            ______________________________________                                          9A                                                                                                           546 (M ##                                                                   + H)                                              - 9B                                                                                                        546 (M + H)                                     - 9C                                                                                                        560 (M + H)                                     - 9D                                                                                                        586 (M + H)                                     - 9E                                                                                                        680 (M + H)                                     - 9F                                                                                                        548 (M + H)                                     - 9G                                                                                                        #STR174##                                       - 9H                                                                                                       ##STR175##                                    ______________________________________                                    

EXAMPLE 10

The following compounds were prepared essentially as described inEXAMPLES 2 and 4.

    __________________________________________________________________________      #STR176##                                                                   Ex. #                                                                            R                 R.sub.6     m/e                                          __________________________________________________________________________      10A                                                                                                            #STR177##                                                                     572 (M ##                                                                   + H)                                            - 10B                                                                                                         #STR179##                                                                     571 (M + H)                                   - 10C                                                                                                         #STR181##                                                                     572 (M + H)                                   - 10D                                                                                                         #STR183##                                                                     586 (M + H)                                   - 10E                                                                                                         #STR185##                                                                     #STR186##                                     - 10F                                                                                                         #STR187##                                                                     #STR188##                                     - 10G                                                                                                         #STR189##                                                                     572 (M + H)                                   - 10H                                                                                                         #STR191##                                                                     586 (M + H)                                   - 10I                                                                                                         #STR193##                                                                     532 (M + H)                                   - 10J                                                                                                         #STR195##                                                                     572 (M + H)                                   - 10J                                                                                                         #STR197##                                                                     586 (M + H)                                   - 10K                                                                                                         #STR199##                                                                     546 (M + H)                                   - 10L                                                                                                         #STR201##                                                                     538 (M + H)                                   - 10M                                                                                                         #STR203##                                                                     644 (M + H)                                   - 10N                                                                                                         #STR205##                                                                     576 (M + H)                                   - 10O                                                                                                         #STR207##                                                                     546 (M + H)                                   - 10P                                                                                                         #STR209##                                                                     #STR210##                                     - 10Q                                                                                                         #STR211##                                                                     560 (M + H)                                   - 10R                                                                                                         #STR213##                                                                     552 (M + H)                                   - 10S                                                                                                         #STR215##                                                                     544 (M + H)                                   - 10T                                                                                                         #STR217##                                                                     546 (M + H)                                   - 10U                                                                                                         #STR219##                                                                     618 (M + H)                                   - 10V                                                                                                         #STR221##                                                                     622 (M + H)                                   - 10W                                                                                                         #STR223##                                                                     598 (M + H)                                   - 10X                                                                                                         #STR225##                                                                     600 (M + H)                                   - 10Y                                                                                                         #STR227##                                                                     602 (M + H)                                __________________________________________________________________________

EXAMPLE 11 ##STR229## (S)-7-chloro-4-[2,2-difluoro-2-(1-methylpiperidin-2-yl)-ethoxy]-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinoline-6-carboxylicacid pyrimidin-4-ylamide

Step 11A7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-2-oxo-1,2-dihydroquinoline-6-carboxylicacid pyrimidin-4-ylamide

To 20 mL dry methylsulfoxide was added sequentially7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-6-iodo-1H-quinolin-2-one(EXAMPLE 4.2 Step B, 1.0 g), 4-dimethylaminopyridine (860 mg),4-aminopyrimidine (90 mg),[1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium (II) and themixture heated to 100° C. under an atmosphere of carbon monoxide. After72 hours, the mixture was cooled to room temperature and poured into 200mL ice/water. The pH of the resulting solution was adjusted to pH4 bythe addition of acetic acid. The resulting solids were collected byfiltration and then re-purified by flash chromatography on silica gel(chlorofonm:methanol, 95:5) to give the title compound (400 mg).

Step 11B(S)-7-chloro-4-[2,2-difluoro-2-(1-methylpiperidin-2-yl)-ethoxy]-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinoline-6-carboxylicacid pyrimidin-4-ylamide

To a solution of (S)-2-(2-chloro-1,1-difluoroethyl)-1-methylpiperidine(39 mg in 1.5 mL N,N-dimethylformamide) was added7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-2-oxo-1,2-dihydroquinoline-6-carboxylicacid pyrimidin-4-ylamide (64 mg), potassium bicarbonate (32 mg) andsodium iodide (25 mg) then heated to 80° C. on an oil bath. After 16hours, the reaction was cooled to room temperature and concentrated invacuo. Purification of the crude product by preparative tic on silicagel (chloroform:2M ammonium in methanol, 97:3) gave the title compound(56 mg). MASS: 582 (M+H)

PREPARATION OF SYNTHETIC INTERMEDIATES(S)-2-(2-chloro-1,1-difluoroethyl)-1-methylpiperidine

Step A (S)-2-(diazoacetyl)piperidine-1-carboxylic acid tert-butyl ester

To a solution of (S)-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester(3.0 g in a mixture of 26 mL dry tetrahydrofuran and 26 mL dry diethylether) at -10° C. was added 1.91 mL of triethylamine followed by thedropwise addition of 1.78 mL isobutyl chloroformate. The reaction wasstirred at -10° C. for 30 minutes then warmed to 0° C. Over the nexthour, 26 mL of a solution of diazomethane in diethyl ether was added(prepared from: 8.0 g Diazald® in 70 mL diethyl ether; 4g potassiumhydroxide; 20 mL 2-(2-ethoxyethoxy)ethanol; 6 mL water and 12 mL diethylether using a mini Diazald Kit) and the mixture allowed to stir at roomtemperature for an additional 2 hours. At this time the reaction wasquenched by the addition of 3 mL acetic acid at 0° C. This was thendiluted with 100 mL water and 100 mL diethyl ether, the layers separatedand the aqueous portion extracted with (2×75 mL) diethyl ether. Thecombined organics were washed with water (75 mL), saturated sodiumbicarbonate (2×75 mL) and brine (75 mL) then dried over magnesiumsulfate. Removal of the solvent in vacuo and purification of the residueby flash chromatography on silica gel (hexane:ethyl acetate, 8:2) gavethe title compound, 2.99 g.

Step B (S)-2-(methoxycarbonylmethyl)piperidine-1-carboxylic acidtert-butyl ester

To a solution of (S)-2-(diazoacetyl)piperidine-1-carboxylic acidtert-butyl ester (5.90 g in 90 mL dry methanol) was added dropwise asolution of silver benzoate (265 mg in 3 mL triethylamine) and themixture stirred at room temperature. After 2 hour, charcoal was addedand the suspension filtered over diatomaceous earth. The mixture wasconcentrated in vacuo and the residue dissolved in ethyl acetate (400mL), washed with water (2×100 mL) and brine (150 mL). The organicportion was dried over magnesium sulfate and the concentrate purified byflash chromatography on silica gel (hexane:ethyl acetate, 8:2) to givethe title compound (5.47 g).

Step C 2-(difluoro-methoxycarbonylmethyl)piperidine-1-carboxylic acidtert-butyl ester To a solution of(S)-2-(methoxycarbonylmethyl)piperidine-1-carboxylic acid tert-butylester (1.0 g in 20 mL dry tetrahydrofuran) at -78° C. was added 19.4 mLof a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene andthe mixture stirred for 30 minutes. At this time, a solution ofN-fluorobenzenesulfonimide (3.06 g in 10 mL dry tetrahydrofuran) wasadded and the mixture stirred at -78° C. for 45 minutes then 0C for anadditional 45 minutes. The reaction was quenched by the addition of 50%saturated ammonium chloride and extracted with diethyl ether (3×100 mL).The combined organics were washed with water, brine and then dried overmagnesium sulfate. Concentration in vacuo gave the crude title compound(1.8 g).

Step D 2,2-difluoro-2-(1 -methylpiperidin-2-yl)ethanol

To a solution of2-(difluoro-methoxycarbonylmethyl)piperidine-1-carboxylic acidtert-butyl ester (1.14 g in 30 mL dry diethyl ether) at 0° C. was added580 mg lithium aluminum hydride and the mixture stirred at lowtemperature. After 15 minutes, the reaction was quenched by thesequential addition of 0.58 mL water, 0.58 mL 2N sodium hydroxide and0.74 mL water. The mixture was stirred vigorously for 1 hour thenfiltered over diatomaceous earth. The filtrate was concentrated in vacuoand purified by flash chromatography on silica gel (hexane:ethylacetate, 85:15) to give the title compound (450 mg).

Step E (S)-2-(2-chloro-1,1-difluoroethyl)-1-methylpiperidine

To a solution of 2,2-difluoro-2-(1-methylpiperidin-2-yl)ethanol (153 mgin 10 mL dry chloroform) was bubbled dry hydrogen chloride gas for aperiod of 5 minutes. To this solution, 0.303 mL of thionyl chloride andthe mixture heated to reflux on an oil bath. After 5 hours, the mixturewas cooled and the solvent removed in vacuo. The residue was re-solvatedin 5 mL ethanol, concentrated in vacuo, re-solvated in ethanol and thentreated with decolorizing carbon. The resulting suspension was filteredover diatomaceous earth and concentrated in vacuo to give the crudetitle compound (200 mg). ##STR230##

Following a procedure similar to that described above and in EXAMPLE 4,the following compounds were prepared:

    __________________________________________________________________________    Ex. #                                                                             R           R.sub.6       m/e                                             __________________________________________________________________________      11A                                                                                                         #STR231##                                                                     506 (M ##                                                                   + H)                                               - 11B                                                                                                      #STR233##                                                                     #STR234##                                        - 11C                                                                                                      #STR235##                                                                     518 (M + H)                                      - 11D                                                                                                      #STR237##                                                                     532 (M + H)                                      - 11E                                                                                                      #STR239##                                                                     550 (M + H)                                      - 11F                                                                                                      #STR241##                                                                     546 (M + H)                                      - 11G                                                                                                      #STR243##                                                                     520 (M + H)                                      - 11H                                                                                                      #STR245##                                                                     546 (M + H)                                      - 11I                                                                                                      #STR247##                                                                     546 (M + H)                                      - 11J                                                                                                      #STR249##                                                                     #STR250##                                        - 11K                                                                                                      #STR251##                                                                     546 (M + H)                                      - 11L                                                                                                      #STR253##                                                                     481 (M + H)                                      - 11M                                                                                                      #STR255##                                                                     561 (M + H)                                      - 11N                                                                                                      #STR257##                                                                     524 (M + H)                                      - 11O                                                                                                      #STR259##                                                                     510 (M + H)                                      - 11P                                                                                                      #STR261##                                                                     538 (M + H)                                      - 11Q                                                                                                      #STR263##                                                                     568 (M + H)                                      - 11R                                                                                                      #STR265##                                                                     524 (M + H)                                   __________________________________________________________________________

EXAMPLE 12 ##STR267##

Following a procedure similar to that described in EXAMPLES 2 and 4, thefollowing compounds were prepared:

    __________________________________________________________________________    Ex. #                                                                            R.sub.6       R.sub.7          R.sub.8                                                                         m/e                                       __________________________________________________________________________      12A H                                                                                                             H 513 (M + H)                              - 12B H                                                                                                          H 513 (M + H)                              - 12C H                                                                                                          H 497 (M + H)                              - 12D H                                                                                                          Cl 547 (M + H)                             - 12E H                                                                                                          Cl 547 (M + H)                             - 12F H                                                                                                          H 545 (M + H)                              - 12F H                                                                                                          Cl 580 (M + H)                             - 12G                                                                                                            CF.sub.3 H 566 (M + H)                     - 12H                                                                                                            CF.sub.3 H 580 (M + H)                     - 12I                                                                                                            Cl H 577 (M + H)                           - 12J                                                                                                            Cl H 563 (M + H)                           - 12K                                                                                                            Cl H 586 (M + H)                        __________________________________________________________________________

EXAMPLE 13 ##STR280##(S)-1-[7-chloro-3-(3,5-dimethylphenyl)-1-methyl-2-oxo-4-(2-piperidin-2-yl-ethoxy)-1,2-dihydroquinolin-6-yl]-1-methyl-3-pyrimidin-4-yl-urea

Step 13A(S)-2-{2-[7-chloro-3-(3,5-dimethylphenyl)-1-methyl-6-(1-methyl-3-pyrimidin-4-yl-ureido)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of lithium bis(trimethylamide) (0.43 mL of a 1M solutionin 1.0 mL dry tetrahydrofuran) at -78° C. was added 0.198 mLhexamethylphosphoramide (HMPA) followed by a solution of(S)-2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(3-pyrimidin-4-yl-ureido)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester (prepared essentially as described in EXAMPLE 1,69 mg in 1.5 mL dry tetrahydrofuran) and the mixture stirred at lowtemperature for 75 minutes. At this time, 0.036 mL of iodomethane wasadded and the mixture warmed to 0° C. After 4 hours, the reaction wasquenched by the addition of IN hydrochloric acid, extracted withmethylene chloride washed with brine and dried over magnesium sulfate.Purification of the concentrate by flash chromatography on silica gel(ethyl acetate:hexane 3:7; then 5:5; then 7:3) gave the title compound(30 mg).

Step 13B(S)-1-[7-chloro-3-(3,5-dimethylphenyl)-1-methyl-2-oxo-4-(2-piperidin-2-yl-ethoxy)-1,2-dihydroquinolin-6-yl]-1-methyl-3-pyrimidin-4-yl-urea

The title compound was prepared essentially as described in EXAMPLE 5,Step B from 30 mg of(S)-2-(2-[7-chloro-3-(3,5-dimethylphenyl)-1-methyl-6-(1-methyl-3-pyrimidin-4-yl-ureido)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl)-piperidine-1-carboxylicacid tert-butyl ester to give the final product (13 mg). MASS: 561 (M+H)##STR281##

Following a procedure similar to that described above, the followingcompounds were prepared:

    ______________________________________                                        Ex. #    R.sub.6           m/e                                                ______________________________________                                          13A                                                                                                      589 (M ##                                                                   + H)                                               ______________________________________                                    

EXAMPLE 14 ##STR283##

Following a procedure similar to that described in EXAMPLES 2, 4 and 11the following compounds were prepared:

    __________________________________________________________________________      Ex. #  R R.sub.6                                                                                                  m/eR284##                               __________________________________________________________________________      14A                                                                                                               #STR285##                                                                     #STR286##                                                                     544 (M ##                                                                   + H)                                         - 14B                                                                                                            #STR288##                                                                     #STR289##                                                                     518 (M + H)                                - 14C                                                                                                            #STR291##                                                                     #STR292##                                                                     524 (M + H)                                - 14D                                                                                                            #STR294##                                                                     #STR295##                                                                     532 (M + H)                             __________________________________________________________________________

What is claimed is:
 1. The compound of the structural formula ##STR297##wherein R is as indicated in the table below:

    ______________________________________                                        Ex. #          R                                                              ______________________________________                                          8A                                                                                           #STR298##                                                       - 8B                                                                                        #STR299##                                                       - 8C                                                                                        #STR300##                                                       - 8D                                                                                        #STR301##                                                       - 8E                                                                                        #STR302##                                                       - 8F                                                                                        #STR303##                                                       - 8G                                                                                        #STR304##                                                       - 8H                                                                                        #STR305##                                                       - 8I                                                                                       ##STR306##                                                    ______________________________________                                    


2. The compound of of the structural formula ##STR307## wherein R₆ is asindicated in the table below:

    ______________________________________                                        Ex. #  R.sub.6                                                                ______________________________________                                          9A                                                                                   #STR308##                                                               - 9B                                                                                #STR309##                                                               - 9C                                                                                #STR310##                                                               - 9D                                                                                #STR311##                                                               - 9E                                                                                #STR312##                                                               - 9F                                                                                #STR313##                                                               - 9G                                                                                #STR314##                                                               - 9H                                                                                #STR315##                                                               - 9I                                                                               ##STR316##                                                            ______________________________________                                    


3. The compound of the structural formula ##STR317## wherein R and R₆are as indicated in the table below:

    ______________________________________                                        Ex. #                                                                              R                  R.sub.6                                               ______________________________________                                          10A                                                                                                   #STR318##                                                                     #STR319##                                              - 10B                                                                                                #STR320##                                                                     #STR321##                                              - 10C                                                                                                #STR322##                                                                     #STR323##                                              - 10D                                                                                                #STR324##                                                                     #STR325##                                              - 10E                                                                                                #STR326##                                                                     #STR327##                                              - 10F                                                                                                #STR328##                                                                     #STR329##                                              - 10G                                                                                                #STR330##                                                                     #STR331##                                              - 10H                                                                                                #STR332##                                                                     #STR333##                                              - 10I                                                                                                #STR334##                                                                     #STR335##                                              - 10J                                                                                                #STR336##                                                                     #STR337##                                              - 10J                                                                                                #STR338##                                                                     #STR339##                                              - 10K                                                                                                #STR340##                                                                     #STR341##                                              - 10L                                                                                                #STR342##                                                                     #STR343##                                              - 10M                                                                                                #STR344##                                                                     #STR345##                                              - 10N                                                                                                #STR346##                                                                     #STR347##                                              - 10O                                                                                                #STR348##                                                                     #STR349##                                              - 10P                                                                                                #STR350##                                                                     #STR351##                                              - 10Q                                                                                                #STR352##                                                                     #STR353##                                              - 10R                                                                                                #STR354##                                                                     #STR355##                                              - 10S                                                                                                #STR356##                                                                     #STR357##                                              - 10T                                                                                                #STR358##                                                                     #STR359##                                              - 10U                                                                                                #STR360##                                                                     #STR361##                                              - 10V                                                                                                #STR362##                                                                     #STR363##                                              - 10W                                                                                                #STR364##                                                                     #STR365##                                              - 10X                                                                                                #STR366##                                                                     #STR367##                                              - 10Y                                                                                                #STR368##                                                                    ##STR369##                                           ______________________________________                                    


4. The compound of the structural formula ##STR370## wherein R and R₆are as indicated in the table below:

    ______________________________________                                        Ex. #  R              R.sub.6                                                 ______________________________________                                          11A                                                                                                 #STR371##                                                                     #STR372##                                                - 11B                                                                                              #STR373##                                                                     #STR374##                                                - 11C                                                                                              #STR375##                                                                     #STR376##                                                - 11D                                                                                              #STR377##                                                                     #STR378##                                                - 11E                                                                                              #STR379##                                                                     #STR380##                                                - 11F                                                                                              #STR381##                                                                     #STR382##                                                - 11G                                                                                              #STR383##                                                                     #STR384##                                                - 11H                                                                                              #STR385##                                                                     #STR386##                                                - 11I                                                                                              #STR387##                                                                     #STR388##                                                - 11J                                                                                              #STR389##                                                                     #STR390##                                                - 11K                                                                                              #STR391##                                                                     #STR392##                                                - 11L                                                                                              #STR393##                                                                     #STR394##                                                - 11N                                                                                              #STR395##                                                                     #STR396##                                                - 11O                                                                                              #STR397##                                                                     #STR398##                                                - 11P                                                                                              #STR399##                                                                     #STR400##                                                - 11Q                                                                                              #STR401##                                                                     #STR402##                                                - 11R                                                                                              #STR403##                                                                     #STR404##                                                - 11S                                                                                              #STR405##                                                                    ##STR406##                                             ______________________________________                                    


5. The compound of the structural formula ##STR407## wherein R₆, R₇ andR₈ is as indicated in the table below:

    ______________________________________                                        Ex. #                                                                              R.sub.6        R.sub.7            R.sub.8                                ______________________________________                                          12A H                                                                                                                H TR408##                               - 12B H                                                                                                             H TR409##                               - 12C H                                                                                                             H TR410##                               - 12D H                                                                                                             Cl R411##                               - 12E H                                                                                                             Cl R412##                               - 12F H                                                                                                             H TR413##                               - 12F H                                                                                                             Cl R414##                               - 12G                                                                                                               CF.sub.3 H                              - 12H                                                                                                               CF.sub.3 H                           ______________________________________                                    


6. The compound of the structural formula ##STR417## wherein R₆ is asindicated in the table below:

    ______________________________________                                        Ex. #     R.sub.6                                                             ______________________________________                                          13A                                                                                     #STR418##                                                            - 13B                                                                                 ##STR419##                                                         ______________________________________                                    


7. The compound of the structural formula ##STR420## wherein R, R₂, R₃,R₄ and R₆ are as indicated in the table below:

    __________________________________________________________________________      Ex. #  R R.sub.6                                                                                        ##STR421##                                        __________________________________________________________________________      14A                                                                                                      #STR422##                                                                     #STR423##                                                                     #STR424##                                        14B                                                                            ## TR425##                                                                       ##STR426##                                                                                ##STR427##                                                       - 14C                                                                                                   #STR428##                                                                     #STR429##                                                                     #STR430##                                           - 14D                                                                                                   #STR431##                                                                     #STR432##                                                                    ##STR433##                                        __________________________________________________________________________


8. A compound of the formula ##STR434## or a pharmaceutically acceptableaddition salt and/or hydrate thereof, or where applicable, a geometricor optical isomer or racemic mixture thereof, wherein R is as indicatedin the table below:

    ______________________________________                                        Ex. #    R                                                                    ______________________________________                                           3A                                                                                    #STR435##                                                             -  3B                                                                                 #STR436##                                                             -  3C                                                                                 #STR437##                                                             -  3D                                                                                 #STR438##                                                             -  3P                                                                                 #STR439##                                                             -  4I                                                                                 #STR440##                                                             -  4EE                                                                                #STR441##                                                             -  4LL                                                                                #STR442##                                                             -  5                                                                                  #STR443##                                                             -  6V                                                                                 #STR444##                                                             -  6W                                                                                 #STR445##                                                             - 12I                                                                                 #STR446##                                                             - 12J                                                                                 #STR447##                                                             - 12K                                                                                ##STR448##                                                          ______________________________________                                    


9. A compound of the formula ##STR449## or a pharmaceutically acceptableaddition salt and/or hydrate thereof, or where applicable, a geometricor optical isomer or racemic mixture thereof, wherein R is as indicatedin the table below:

    ______________________________________                                        Ex. #      R                                                                  ______________________________________                                          9G                                                                                      ##STR450##                                                        ______________________________________                                    


10. The compound the structural formula ##STR451## wherein R₆ is asindicated in the table below:

    ______________________________________                                        Ex. #       R.sub.6                                                           ______________________________________                                          1A                                                                                        #STR452##                                                          - 1B                                                                                     #STR453##                                                          - 1C                                                                                     #STR454##                                                          - 1D                                                                                     #STR455##                                                          - 1E                                                                                     #STR456##                                                          - 1F                                                                                     #STR457##                                                          - 1G                                                                                     #STR458##                                                          - 1H                                                                                     #STR459##                                                          - 1I                                                                                     #STR460##                                                          - 1J                                                                                     #STR461##                                                          - 1K                                                                                     #STR462##                                                          - 1L                                                                                     #STR463##                                                          - 1M                                                                                     #STR464##                                                          - 1N                                                                                     #STR465##                                                          - 1O                                                                                     #STR466##                                                          - 1P                                                                                     #STR467##                                                          - 1Q                                                                                     #STR468##                                                          - 1R                                                                                     #STR469##                                                          - 1S                                                                                     #STR470##                                                          - 1T                                                                                     #STR471##                                                          - 1U                                                                                     #STR472##                                                          - 1V                                                                                     #STR473##                                                          - 2A                                                                                     #STR474##                                                          - 2B                                                                                     #STR475##                                                          - 2C                                                                                     #STR476##                                                          - 2D                                                                                     #STR477##                                                          - 2E                                                                                     #STR478##                                                          - 2F                                                                                     #STR479##                                                          - 2G                                                                                     #STR480##                                                          - 2H                                                                                     #STR481##                                                          - 2I                                                                                     #STR482##                                                          - 2J                                                                                     #STR483##                                                          - 2K                                                                                     #STR484##                                                          - 2L                                                                                     #STR485##                                                          - 3E                                                                                     #STR486##                                                          - 3F                                                                                     #STR487##                                                          - 3G                                                                                     #STR488##                                                          - 3H                                                                                     #STR489##                                                          - 3I                                                                                     #STR490##                                                          - 3J                                                                                     #STR491##                                                          - 3K                                                                                     #STR492##                                                          - 3L                                                                                     #STR493##                                                          - 3M                                                                                     #STR494##                                                          - 3N                                                                                     #STR495##                                                          - 3O                                                                                     #STR496##                                                          - 4A                                                                                     #STR497##                                                          - 4B                                                                                     #STR498##                                                          - 4C                                                                                     #STR499##                                                          - 4D                                                                                     #STR500##                                                          - 4E                                                                                     #STR501##                                                          - 4F                                                                                     #STR502##                                                          - 4G                                                                                     #STR503##                                                          - 4H                                                                                     #STR504##                                                          - 4J                                                                                     #STR505##                                                          - 4K                                                                                     #STR506##                                                          - 4L                                                                                     #STR507##                                                          - 4M                                                                                     #STR508##                                                          - 4N                                                                                     #STR509##                                                          - 4O                                                                                     #STR510##                                                          - 4P                                                                                     #STR511##                                                          - 4Q                                                                                     #STR512##                                                          - 4R                                                                                     #STR513##                                                          - 4S                                                                                     #STR514##                                                          - 4T                                                                                     #STR515##                                                          - 4U                                                                                     #STR516##                                                          - 4V                                                                                     #STR517##                                                          - 4W                                                                                     #STR518##                                                          - 4X                                                                                     #STR519##                                                          - 4Y                                                                                     #STR520##                                                          - 4Z                                                                                     #STR521##                                                          - 4AA                                                                                    #STR522##                                                          - 4BB                                                                                    #STR523##                                                          - 4CC                                                                                    #STR524##                                                          - 4DD                                                                                    #STR525##                                                          - 4FF                                                                                    #STR526##                                                          - 4GG                                                                                    #STR527##                                                          - 4HH                                                                                    #STR528##                                                          - 4II                                                                                    #STR529##                                                          - 4JJ                                                                                    #STR530##                                                          - 4KK                                                                                    #STR531##                                                          - 4MM                                                                                    #STR532##                                                          - 4NN                                                                                    #STR533##                                                          - 4OO                                                                                    #STR534##                                                          - 4PP                                                                                    #STR535##                                                          - 6A                                                                                     #STR536##                                                          - 6B                                                                                     #STR537##                                                          - 6C                                                                                     #STR538##                                                          - 6D                                                                                     #STR539##                                                          - 6E                                                                                     #STR540##                                                          - 6F                                                                                     #STR541##                                                          - 6G                                                                                     #STR542##                                                          - 6H                                                                                     #STR543##                                                          - 6I                                                                                     #STR544##                                                          - 6J                                                                                     #STR545##                                                          - 6K                                                                                     #STR546##                                                          - 6L                                                                                     #STR547##                                                          - 6M                                                                                     #STR548##                                                          - 6N                                                                                     #STR549##                                                          - 6O                                                                                     #STR550##                                                          - 6P                                                                                     #STR551##                                                          - 6Q                                                                                     #STR552##                                                          - 6R                                                                                     #STR553##                                                          - 6S                                                                                     #STR554##                                                          - 6T                                                                                     #STR555##                                                          - 6U                                                                                     #STR556##                                                          - 6X                                                                                     #STR557##                                                          - 6Y                                                                                     #STR558##                                                          - 6Z                                                                                     #STR559##                                                          - 7A                                                                                     #STR560##                                                          - 7B                                                                                     #STR561##                                                          - 7C                                                                                     #STR562##                                                          - 7D                                                                                     #STR563##                                                          - 7E                                                                                     #STR564##                                                          - 7F                                                                                     #STR565##                                                          - 7G                                                                                     #STR566##                                                          - 7H                                                                                    ##STR567##                                                       ______________________________________                                    